2 

1. EPA ignored genetic evidence of vulnerable populations 

2. EPA needlessly delayed a decision regarding endocrine disrupting effects 

3. EPA ignored data regarding cancer risks 

4. EPA’s CRA misrepresented risks, failed to apply FQPA 10X safety factor3

5. EPA over-relied on registrant data 

6. EPA failed to properly address the exporting hazard from chlorpyrifos 

7. EPA failed to quantitatively incorporate data demonstrating long-lasting effects from 

early life exposure to chlorpyrifos in children 

8. EPA disregarded data demonstrating that there is no evidence of a safe level of exposure 

during pre-birth and early life stages 

9. EPA failed to cite or quantitatively incorporate studies and clinical reports suggesting 

potential adverse effects below 10% cholinesterase inhibition 

10. EPA failed to incorporate inhalation routes of exposure 

This partial Agency response to the petition addresses the first six claims listed above: 

genetic evidence of vulnerable populations; endocrine disrupting effects; cancer risks; CRA 

misrepresents risks, fails to apply FQPA 10X safety factor; over-reliance on registrant data; and 

exporting hazard. EPA’s response to three of petitioners’ remaining four claims -- that EPA 

failed to quantitatively incorporate data exhibiting long-lasting effects from early life exposure to 

chlorpyrifos in children; that EPA disregarded data demonstrating that there is no evidence of a 

safe level of exposure during pre-birth and early life stages; and that EPA failed to cite or 

quantitatively incorporate studies and clinical reports suggesting potential adverse effects below 

10% cholinesterase inhibition -- involve highly complex assessments, using precedent setting 

risk assessment methodologies. For this reason, consistent with EPA’s external scientific peer 

review policy, the Agency sought advice on these issues from the Federal Insecticide, Fungicide, 

and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) at a meeting that occurred April 

10-13, 2012. As to the petitioners’ fourth remaining claim -- that EPA failed to incorporate 

inhalation routes of exposure -- EPA is today releasing its “Evaluation of the Potential Risks 

From Spray Drift and the Impacts of Potential Risk Reduction Measures”4

 that further refines its 

analysis of spray drift from chlorpyrifos that was presented in the preliminary human health risk 

assessment (HHRA) released in July 2011. In connection with this spray drift assessment, the 

chlorpyrifos registrants have agreed to implement label mitigation (in the form of rate reductions 

and spray drift buffers) that will reduce risks to bystanders from spray drift. EPA’s spray drift 

assessment and the associated mitigation action are not intended to provide a complete response 

to petitioners’ fourth claim since this mitigation action does not take into account potential 

exposures from volatilization following chlorpyrifos applications. That work is ongoing. 

Further, the spray drift risk assessment may be impacted by those issues reviewed by the recent 

SAP. Accordingly, the Agency will address this claim fully when it provides its complete 

response in December 2012. 

 

3

 For convenience’s sake, the legal requirements regarding the additional safety margin for infants and children in 

section 408(b)(2)(C) are referred to throughout this response as the “FQPA 10X safety factor” or simply the “FQPA 

safety factor. Due to Congress’ focus on both pre- and post-natal toxicity, EPA has interpreted this additional safety 

factor as pertaining to risks to infants and children that arise due to pre-natal exposure as well as to exposure during 

childhood years. 

4

 Available at http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2008-0850. 
3 

In connection with this peer review process, the Agency has recently received the final 

SAP report5, dated July 11, 2012. EPA will carefully review and consider the SAP’s 

recommendations in developing the Agency’s response to the remaining petition issues while 

also informing the final human health risk assessment for the statutorily mandated registration 

review program. Following EPA's complete written response to the petition, which it plans to 

provide petitioners by the end of this year, EPA intends to work to complete its human health 

risk assessment in connection with the registration review of chlorpyrifos under section 3(g) of 

FIFRA. That assessment will include consideration of issues not raised in the petition, including 

human dietary exposures from drinking water. It is important to note, however, that EPA may 

take regulatory action at any time if and when it determines that existing tolerances are unsafe or 

that chlorpyrifos presents unreasonable adverse effects on the environment. 

 

 The first section of this response provides the applicable statutory and regulatory 

background. The second section discusses this petition in the context of the legal framework of 

FIFRA and FFDCA. The third section discusses the regulatory background for chlorpyrifos. 

The fourth section contains EPA’s response to each of the six issues identified above. The final 

section is the conclusion. 

I. Statutory and Regulatory Background/Framework 

A. FFDCA/FIFRA and Applicable Regulations 

EPA establishes maximum residue limits, or ‘‘tolerances,’’ for pesticide residues in food 

and feed commodities under section 408 of the FFDCA.6 Without such a tolerance or an 

exemption from the requirement of a tolerance, a food containing a pesticide residue is 

‘‘adulterated’’ under section 402 of the FFDCA and may not be legally moved in interstate 

commerce.7 Monitoring and enforcement of pesticide tolerances are carried out by the U.S. 

Food and Drug Administration and the U.S. Department of Agriculture. Section 408 was 

substantially rewritten by the Food Quality Protection Act of 1996 (FQPA), which added the 

provisions discussed below establishing a detailed safety standard for pesticides, additional 

protections for infants and children, and the estrogenic substances screening program.8

EPA also regulates pesticides under the FIFRA.9

 While the FFDCA authorizes the 

establishment of legal limits for pesticide residues in food, FIFRA requires the approval of 

pesticides prior to their sale and distribution,10 and establishes a registration regime for 

regulating the use of pesticides. FIFRA regulates pesticide use in conjunction with its registration 

scheme by requiring EPA review and approval of pesticide labels and specifying that use of a 

pesticide inconsistent with its label is a violation of federal law.11 In the FQPA, Congress 

integrated action under the two statutes by requiring that the safety standard under the FFDCA 

be used as a criterion in FIFRA registration actions as to pesticide uses which result in dietary 

 

5

 Available at http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2012-0040-0029 6

 21 U.S.C. 346a 

7

 21 U.S.C. 331, 342 

8

 Public Law 104– 170, 110 Stat. 1489 (1996). 

9

 7 U.S.C. 136 et seq. 

10 7 U.S.C. 136a(a). 

11 7 U.S.C. 136j(a)(2)(G). 
4 

risk from residues in or on food,12 and directing that EPA coordinate, to the extent practicable, 

revocations of tolerances with pesticide cancellations under FIFRA.13 

In addressing the review of petitions, however, Congress has expressly provided that any 

issue that can be raised through the FFDCA review process can only be reviewed through that 

process.

14 Accordingly, to the extent a petition to revoke tolerances and cancel registrations 

raises issues relevant to the establishment or revocation of tolerances, EPA’s response to those 

issues may be challenged only through the administrative and judicial review procedures 

provided in section 408 of the FFDCA and are not reviewable under FIFRA or any other 

provision of law. 

II. Legal Framework and the NRDC and PANNA Petition 

 A. FFDCA 

 

All but one of the issues raised in the petition relate to EPA's establishment of tolerances 

under the FFDCA. For this reason, as explained in section I, the FFDCA directs that 

consideration of these petition issues be undertaken under FFDCA section 408. Under the 

FFDCA, EPA takes final action on a petition to revoke tolerances by either issuing an order in 

the Federal Register denying the petition or by publishing a final rule revoking the tolerances. 

EPA does not intend to issue a formal denial in the Federal Register for the five issues addressed 

in this response that are subject to FFDCA review until after it completes its review of the four 

remaining petition issues. That way, petitioners will not be compelled to assess whether to file 

objections to EPA’s responses on separate occasions and EPA will not be compelled to produce 

separate responses. However, if petitioners wish to begin the objections process on today’s 

partial response, EPA will publish a formal denial order for those claims. As explained 

previously, EPA intends to address, in writing, the remaining issues raised in the petition by 

December 2012. Following this written response, to the extent EPA denies the petition, EPA 

would expect to publish any denial order by February 2013. While the December response will 

address all the remaining issues raised in the petition, it is possible that EPA will not be taking 

final agency action on all the petition issues immediately following the December 2012 response. 

While petitioners have raised a number of issues related to the assessment of the toxicity 

of chlorpyrifos, the petition did not address in any detail, dietary exposure to chlorpyrifos that 

must be taken into account in determining whether tolerances are safe. Reassessing the exposure 

to chlorpyrifos is one of the issues EPA intends to address in the registration review assessment 

of the chemical, which is currently underway. It is possible that if EPA concludes that the 

toxicity profile of chlorpyrifos needs to be modified based upon this reassessment, the final 

decision on the petition would need to wait for the conclusion of the chlorpyrifos exposure 

reassessment under the registration review program. The registration review assessment will 

include consideration of issues not raised in the petition, including human dietary exposures from 

drinking water. It is important to note, however, that EPA may take regulatory action at any time 

 

12 7 U.S.C. 136(bb). 

13 21 U.S.C. 346a(l)(1). 

14 21 U.S.C. 346a(h)(5); NRDC v. Johnson, 461 F.3d 164, 176 (2d Cir. 2006). 
5 

if and when it determines that existing tolerances are unsafe or that chlorpyrifos presents 

unreasonable adverse effects on the environment. 

Tolerances are established, amended, or revoked by rulemaking under the unique 

procedural framework set forth in the FFDCA. Generally, a tolerance rulemaking is initiated by 

the party seeking to establish, amend, or revoke a tolerance by means of filing a petition with 

EPA.15 EPA publishes in the Federal Register a notice of the petition filing and requests public 

comment.16 After reviewing the petition, and any comments received on it, EPA may issue a 

final rule establishing, amending, or revoking the tolerance, issue a proposed rule to do the same, 

or deny the petition.17

Once EPA takes final action on the petition by establishing, amending, or revoking the 

tolerance or denying the petition, any party may file objections with EPA and seek an evidentiary 

hearing on those objections.18 Objections and hearing requests must be filed within 60 days.19 

The statute provides that EPA shall ‘‘hold a public evidentiary hearing if and to the extent the 

Administrator determines that such a public hearing is necessary to receive factual evidence 

relevant to material issues of fact raised by the objections.’’20 EPA regulations make clear that 

hearings will only be granted where it is shown that there is ‘‘a genuine and substantial issue of 

fact,’’ the requestor has identified evidence ‘‘which, if established, resolve one or more of such 

issues in favor of the requestor,’’ and the issue is ‘‘determinative’’ with regard to the relief 

requested.21 Further, a party may not raise issues in objections unless they were part of the 

petition and an objecting party must state objections to the EPA decision and not just repeat the 

allegations in its petition.22 EPA’s final order on the objections is subject to judicial review in 

the U.S. Court of Appeals.23

B. FIFRA and Exporting Hazard 

The exporting hazard issue raised in the petition is the sole claim that raises issues that 

are subject to FIFRA review. Petitioners claim that “unless chlorpyrifos is banned, and all 

tolerances cancelled [sic], chlorpyrifos will continue to be used, often unsafely, in other countries 

thus creating a health and environmental hazard in those countries and on contaminated food reentering the US.”24 While the claim includes a request to both cancel registrations and revoke 

tolerances, the policy arguments raised in the petition regarding the consideration of the 

international impacts of the U.S. registration of chlorpyrifos are not relevant to the establishment 

of tolerances under the FFDCA. FIFRA Section 6 authorizes EPA to cancel pesticide 

registrations that do not comply with FIFRA and, in certain circumstances, to suspend those 

registrations pending the completion of cancellation proceedings. EPA takes final Agency action 

 

15 See 21 U.S.C. 346a(d)(1). 

16 21 U.S.C. 346a(d)(3). 

17 21 U.S.C. 346a(d)(4). 

18 21 U.S.C. 346a(g)(2). 

19 Id. 20 21 U.S.C. 346a(g)(2)(B). 

21 40 CFR 178.32(b) 

22 See Nat’lCorn Growers Assoc., et al. v. EPA 613 F.3d 266 (D.C. Cir. 2010). 23 21 U.S.C. 346a(h)(1). 

24 Petition at 21. 
6 

when it issues a response to petitioners either denying their petition or by initiating and 

completing the cancellation process under FIFRA. 

EPA considers this portion of the response to NRDC’s petition to be a final action, and 

believes the petitioner may challenge now this portion of the Agency’s petition denial in federal 

court pursuant to section 16 of FIFRA. Because, as explained below, EPA is today denying 

petitioners’ request to cancel on the basis of the export hazard issue, this letter will constitute a 

final Agency action as it relates to that specific issue. As noted, the remaining issues are subject 

to review as provided in section 408 of the FFDCA. 

III. Background 

 In 2000, the chlorpyrifos technical registrants entered into an agreement with the Agency 

regarding the use of chlorpyrifos which eliminated virtually all homeowner residential uses, 

phased-out all termiticide uses, eliminated use on tomatoes, and changed use on grapes and 

apples from a foliar use to a dormant use. 

In September 2001, the Agency completed its IRED for chlorpyrifos. At the time of the 

IRED the Agency was also working on the OP CRA, which addresses all those OP pesticides 

sharing the common mechanism endpoint, acetylcholinesterase (AChE) inhibition. Specifically, 

the members of this class share the ability to bind to and phosphorylate the enzyme AChE in 

both the central (brain) and peripheral nervous systems. 

In August 2006, the Agency released its 2006 Update to the OP CRA. With EPA’s 2006 

release of the OP CRA, all reregistration eligibility decisions (REDs) for individual OP 

pesticides, including chlorpyrifos, were considered complete. OP IREDs, therefore, were 

considered completed REDs. 

In September 2007, EPA received NRDC and PANNA’s joint petition to revoke all 

tolerances and cancel all registrations for chlorpyrifos. The petition largely challenged the 

conclusions of the Agency’s IRED and 2006 OP CRA. 

Although EPA completed reregistration and tolerance reassessment for the OP pesticides 

in 2006, the Agency made the decision to move chlorpyrifos and other OP pesticides forward in 

the re-evaluation schedule so that they began registration review in 2008 and 2009. The 

chlorpyrifos registration review docket opened in 2009. 

In connection with its ongoing re-evaluation of chlorpyrifos and analyses of the complex 

issues raised in the petition, in 2008 EPA convened an SAP meeting to review a draft science 

issue paper on the human health effects of chlorpyrifos to provide a preliminary review of the 

scientific literature on experimental toxicology and epidemiology studies available at that time. 

Specifically, the focus was on studies that evaluated the effects of chlorpyrifos on infants and 

children from in utero and/or post-natal exposures and on studies that evaluated population 

variability with respect to response to paraxonase (PON1). In summary, the SAP expressed 

confidence that the studies conducted by Columbia University are epidemiologically sound. The 

SAP agreed with the Agency that human epidemiological studies have utility for risk 
7 

characterization, but not as the principal basis for establishing the point of departure (PoD), in 

part due to uncertainty in attributing observed adverse neurodevelopmental effects in children 

solely to chlorpyrifos, when exposure was to multiple anticholinesterase insecticides.25

In December 2009, EPA convened a SAP to review scientific issues associated with 

interpreting risks related to the field volatilization of conventional pesticides.26 The objectives of 

the meeting were to review both the exposure and hazard aspects of the risk assessment process. 

The primary focus of the discussion on exposure assessment was on methods for predicting 

emissions from treated fields in lieu of having actual field volatilization studies as well as how 

such information should be considered in exposure assessment. With regard to hazard 

evaluations, the impact on inhalation risk estimates based on differences in how doses are 

experimentally administered to rodents (oral or inhalation) was considered. The Agency’s goal 

for the SAP review was to receive feedback on procedures, methodologies, and data inputs to 

inform the assessment of bystander exposure resulting from field volatilization of conventional 

pesticides. The procedures, refined in part from the SAP’s feedback, will inform the Agency’s 

analysis as it considers chlorpyrifos emissions data identified in the literature, as well as data 

from a field study Dow Agrosciences undertook and submitted to the Agency on July 6, 2012. 

In February 2010, EPA convened an SAP to review the Agency’s draft “Framework for 

Incorporating Human Epidemiologic & Incident Data in Health Risk Assessment,”27 which 

provides the conceptual foundation for evaluating multiple lines of scientific evidence in a 

human health risk assessment. This draft framework draws from the mode of action 

framework28 and its use of the modified Bradford Hill Criteria29 and, thus, explicitly considers 

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

plausibility. 

 

25 U.S. EPA (2008). Transmittal of Meeting Minutes of the FIFRA Scientific Advisory Panel Meeting Held 

September 16-18, 2008 on the Agency’s Evaluation of the Toxicity Profile of Chlorpyrifos. Available at 

http://www.epa.gov/scipoly/sap/meetings/2008/september/sap0908report.pdf 26 U.S. EPA (2009). Transmittal of Meeting Minutes of the FIFRA SAP Meeting Held December 1-3, 2009 on the 

Scientific Issues Associated with “Field Volatilization of Conventional Pesticides.” Available at 

http://www.epa.gov/scipoly/sap/meetings/2009/december/120309meetingminutes.pdf 27 U.S. EPA (2010). Transmittal of Meeting Minuets of the FIFRA Scientific Advisory Panel Meeting on the Draft 

Framework and Case Studies on Atrazine, Human Incidents, and the Agricultural Health Study: Incorporation of 

Epidemiology and Human Incident Data into Human Health Risk Assessment. Available at 

http://www.epa.gov/scipoly/sap/meetings/2010/020210minutes.pdf

28 U.S. EPA (2007). Framework for Determining a Mutagenic Mode of Action for Carcinogenicity: Using EPA’s 

2005 Cancer Guidelines and Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to 

Carcinogens. Available at http://www.epa.gov/osa/mmoaframework/pdfs/MMOA-ERD-FINAL-83007.pdf

29 U.S. EPA (1999). Guidelines for Carcinogen Risk Assessment, Risk Assessment Forum, SAB Review Draft. 

Available at http://www.epa.gov/cancerguidelines/draft-guidelines-carcinogen-ra-1999.htm; Sonich-Mullin, C., R. 

Fielder, J. Wiltse et al, 2001. IPCS conceptual framework for evaluating a mode of action for chemical 

carcinogenesis. Regul Toxicol Pharmacol. 34:146-152 Meek, M.E., J.R. Bucher, S.M. Cohen et al, 2003. A 

framework for human relevance analysis of information on carcinogenic modes of action. Crit. Rev. Toxicol. 

33:591-653; Seed, J., E.W. Carney, R.A. Corley et al., 2005. Overview: Using mode of action and lifestage 

information to evaluate the human relevance of animal toxicity data. Crit. Rev. Toxicol. 35(8-9):664-672; U.S. 

EPA (2005). Guidelines for Carcinogen Risk Assessment. Available at 

http://www.epa.gov/raf/publications/pdfs/CANCER_GUIDELINES_FINAL_3-25-05.PDF
8 

In July 2011, the Agency released the preliminary HHRA for chlorpyrifos for public 

comment. The comment period officially closed on October 6, 2011. The Agency received 48 

unique comments totaling over 1000 pages, which included a number of significant study 

citations. The Agency continues to work on reviewing the public comments and studies cited to 

further inform the final HHRA for chlorpyrifos. 

Since the 2008 SAP on chlorpyrifos, and in part due to the SAP’s feedback, the Agency 

has performed further analyses on the existing and new epidemiology studies with mothers and 

children, available biomonitoring data, and experimental toxicology studies evaluating proposed 

adverse outcome pathways in the context of human health risk assessment. Specifically, the 

Agency is evaluating available literature on the potential for chlorpyrifos to cause long term 

adverse effects from early life exposure, in vivo and in vitro studies evaluating mechanistic 

aspects of chlorpyrifos, and the potential for adverse effects below PoDs established from 

cholinesterase inhibition used for regulatory purposes. This analysis is complicated and 

multifaceted as it involves many lines of scientific evidence (i.e., in vivo & in vitro experimental 

toxicology studies, explicit consideration of adverse outcome pathway framework analyses, 

exposure, human epidemiology, and biomonitoring data). As the Agency works to finalize the 

HHRA and respond to the remaining petition issues, the Agency is working towards a weight of 

evidence evaluation integrating the epidemiology studies with the experimental toxicology 

studies for the neurodevelopmental outcomes. As noted previously the Agency convened a 

FIFRA SAP in April 2012 to review the Agency’s analyses to ensure it is utilizing sound science 

in making its regulatory determinations and has recently received the final SAP report, dated 

July 11, 2012, of that meeting. 

IV. Petition Response 

1. Genetic Evidence of Vulnerable Populations

a. Petitioners’ claim 

Petitioners claim that the Agency failed to calculate an appropriate intra-species 

uncertainty factor (i.e., within human variability) for chlorpyrifos in both its aggregate and 

cumulative assessments.30 They assert that certain relevant, robust data, specifically the Furlong 

et al. (2006) study31 that addresses intra-species variability in the behavior of the detoxifying 

enzyme PON1, indicates that the Agency should have applied an intra-species safety factor “of at 

least 150X in the aggregate and cumulative assessments” rather than the 10X factor EPA 

applied.32 Petitioners conclude by noting that applying an intra-species factor of 100X or higher 

would require setting tolerances below the level of detection, which therefore should compel 

EPA to revoke all chlorpyrifos tolerances. 

 

30Petition at 6. 

31 Furlong CE, Holland N, Richter RJ, Bradman A, Ho A, Eskenazi B (2006). PON1status of farmworker mothers 

and children as a predictor of organophosphate sensitivity. Pharmacogenet Genomics. 2006 Mar; 16(3):183-90. 32 Petition at 6. 
9 

 b. Agency Response

Petitioners are correct that the Agency, as part of the 2006 OP CRA, evaluated, but did 

not rely on Furlong et al. in setting the intra-species uncertainty factor for that assessment. The 

Agency did not rely on the results of the PON1 data in the OP CRA because these data do not 

take into consideration the complexity of OP pesticide metabolism, which involves multiple 

metabolic enzymes, not just PON1. In addition, EPA believes the methodology utilized in the 

Furlong et al. study to measure intra-species variability – i.e., combining values from multiple 

species to determine the range of sensitivity within a single species – is not consistent with wellestablished international risk assessment practices. Further, EPA believes that petitioners’ 

assertion that the Furlong et al. study supports an intra-species uncertainty factor of at least 150X 

is based on an analysis of the data that is inconsistent with EPA policy and widely- accepted 

international guidance on the development of intra-species uncertainty factors. For these 

reasons, as further explained below, EPA believes it is not appropriate to rely on the results of 

the Furlong et al. study, or petitioners’ interpretation of those results, for purposes of determining 

the intra-species uncertainty factor. At this time, there is not a reasonable scientific basis for 

departing from the standard 10-fold intra-species uncertainty factor for extrapolating variability 

based on PON1. 

Addressing human variability and sensitive populations is an important aspect of the 

Agency’s risk assessment process. The Agency is well aware of the issue of PON1 and has 

examined the scientific evidence on this source of genetic variability. PON1 is one of the key 

detoxification enzymes of chlorpyrifos. Specifically, PON1 is an A-esterase which can 

metabolize chlorpyrifos oxon without inactivating the enzyme.33 Indeed, as part of the 2008 

SAP, EPA performed a literature review of PON1 and its possible use in informing the intraspecies (i.e., within human variability) uncertainty factor. This literature review can be found in 

the draft Appendix E: Data Derived Extrapolation Factor Analysis to the draft Science Issue 

Paper: Chlorpyrifos Hazard and Dose Response Characterization.34 In sum, the Agency 

considered available PON1 data from more than 25 studies from diverse human populations 

worldwide. 

The Agency focused on the PON1-192 polymorphism since it has been linked to 

chlorpyrifos oxon sensitivity in experimental toxicology studies and, has been evaluated in 

epidemiology studies attempting to associate PON1 status with health outcomes following OP 

pesticide exposure in adults and children (Holland et al., 200635; Chen et al., 2003).36 However, 

 

33 Sultatos LG; Murphy SD, (1983). Kinetic Analysis Of The Microsomal Biotransformation Of The 

Phosphorothioate Insecticides Chlorpyrifos And Parathion. Fundemental and Applied Toxicology. 3:16-21. 

34 U.S. EPA (2008). Draft Appendix E available at 

http://www.epa.gov/scipoly/sap/meetings/2008/september/appendixe.pdf . Draft Science Issue Paper: Chlorpyrifos 

Hazard and Dose Response Characterization. August 21, 2008. Available at 

http://www.epa.gov/scipoly/sap/meetings/2008/september/chlorpyrifoscharacter.pdf 35 Note, Holland et al (2006) and Furlong et al (2006) report findings from the same cohort. The Holland reference 

provides enzymes activities for specific polymorphisms in Table 4; the Furlong paper does not report such values 

and provides information primarily in graphical form. 

36 Holland, N., Furlong, C., Bastaki, M., Richter, R., Bradman, A., Huen, K., Beckman, K., and Eskenazi, B. (2006). 

Paraoxonase polymorphisms, haplotypes, and enzyme activity in Latino mothers and newborns. Environ. Health 

Perspect. 114(7), 985-991; Chen, J., Kumar, M., Chan, W., Berkowitz, G., and Wetmur, J. (2003). Increased 

Influence of Genetic Variation on PON1 Activity in Neonates. Environmental Health Perspective 111, 11:1403-9 
10 

EPA believes that focusing on PON1 variability in isolation from other metabolic action is not an 

appropriate approach for developing a data-driven uncertainty factor. The Agency solicited 

feedback from the SAP on the utility of the PON1 data, by itself, for use in risk assessment; the 

SAP was similarly not supportive of using such data in isolation. Specifically the SAP report 

states: 

“...the information on PON1 polymorphisms should not be used as the sole 

factor in a data-derived uncertainty factor for two main reasons: 1) it is only 

one enzyme in a complex pathway, and is subsequent to the bioactivation 

reaction; therefore it can only function on the amount of bioactivation product 

(i.e., chlorpyrifos-oxon) that is delivered to it by CYP450); and 2) the genotype 

of PON1 alone is insufficient to predict vulnerability because the overall level 

of enzyme activity is ultimately what determines detoxification potential from 

that pathway; thus, it is better to use PON1 status because it provides 

information regarding PON1 genotype and activity. Some of the data from 

laboratory animal studies in PON knockout animals are using an unrealistic 

animal model and frequently very high dose levels, and do not reflect what 

might happen in humans.” 37

Based on a detailed review of the literature and the comments from the SAP, the Agency 

has determined that such data are not appropriate for use alone in deriving an intra-species 

uncertainty factor for use in human health risk assessment. As indicated by the SAP report, 

multiple factors (e.g., other enzymes such as P450s, carboxylesterases, butyrlcholinesterase) are 

likely to impact potential population sensitivity, rendering the results of the PON1 data, by 

themselves, insufficiently reliable to support a regulatory conclusion about the potential variation 

of human sensitivity to chlorpyrifos. It is noteworthy that a recent report by the CDC-ATSDR,38

is in agreement with EPA’s conclusion. It states that the “correlation between PON-1 genotype, 

cholinesterase activity, and clinical toxicity needs to be further evaluated.” Population 

variability data on PON1 would be more useful incorporated into a physiologically-based 

pharmacokinetic model which would account for all the metabolic processes relevant for 

chlorpyrifos at a range of dose levels. 

Since the 2008 SAP, several epidemiological studies have been published that considered 

the association between PON1 status/genotype and health outcome. Hofmann et al. (2009) 

recently reported associations between PON1 status and inhibition of butyrylcholinesterase in a 

group of pesticide handlers in Washington. The authors note that this study requires replication 

with larger sample size(s) and more blood samples.39 Given the limitations of Hofmann et al., 

 

37 U.S. EPA (2008). Transmittal of Meeting Minutes of the FIFRA Scientific Advisory Panel Meeting Held 

September 16-18, 2008 on the Agency’s Evaluation of the Toxicity Profile of Chlorpyrifos. Available at 

http://www.epa.gov/scipoly/sap/meetings/2008/september/sap0908report.pdf at 61. 38 Matthews, A.R., Sutter, M.E., Rentz, D.E. (2011) Serum Paraoxonase-1 (PON-1) Genotype and Exposure to 

Organophosphorous Insectides—Is There a High-Risk Population? J. Med. Toxicol. (2011) 7:243–247 DOI 

10.1007/s13181-011-0166-2. 

39 Hofmann, J.N., Keifer, M.C., Furlong, C.E., De Roos, A.J., Farin., F.M., Fenske, R.A., van Belle, G., Checkoway, 

H. (2009) Serum Cholinesterase Inhibition in Relation to Paraoxonase-1 (PON1) Status among OrganophosphateExposed Agricultural Pesticide Handlers./ Environ Health Perspect 117:1402–1408 (2009). 

doi:10.1289/ehp.0900682. Available at http://dx.doi.org/ [Online 9 June 2009]. 
11 

the Agency has not drawn any conclusions from this study. The Q/R-192 and/or C/T -108 

polymorphism at the promoter site have been evaluated recently as a factor affecting birth or 

neurobehavioral outcomes following gestational exposure to OP pesticides.40 These studies 

(Eskanazi., et al., 2010; Harley et al., 2011; Engel et al., 2011) were evaluated by EPA in 

preparation for the April 2012 SAP review. 

Petitioners further emphasize that the Furlong et al. study supports an intra-species 

uncertainty factor of over 164X given the range of variability seen in that study. The 164X value 

is derived from sensitivity observed in transgenic mice expressing human PON1Q-192 compared 

with mice expressing human PON1R-192 combined with the range of plasma arylesterase from 

the newborn with the lowest PON1 level compared with the mother with the highest PON1 level 

from a group of 130 maternal-newborn pairs from the CHAMACOS (Center for the Health 

Assessment of Mothers and Children of Salinas) cohort. 

EPA believes it is fundamentally at odds with international risk assessment practices to 

combine values from both mouse and human data to determine the potential range of variability 

within a single species – regardless of whether the test animals express a human PON1 enzyme. 

As the 2008 FIFRA SAP explained, PON1 is but a single enzyme that should not be considered 

in isolation to predict the overall level of enzyme activity that may affect human sensitivity to a 

substance. Using a 164X intra-species uncertainty factor derived from the Furlong et al. study 

would take this practice one step further by relying upon combined PON1 values from different 

species with differing overall metabolic activity to derive the intra-species factor. EPA does not 

believe this approach is an appropriate means of determining the potential range of intra-species 

variability. 

Finally, petitioners’ assertion that the Furlong study supports an intra-species uncertainty 

factor of at least 150X is based on an analysis of that study that is inconsistent with EPA policy 

and widely- accepted international guidance on the development of intra-species uncertainty 

factors. In deriving the intra-species uncertainty factor in its risk assessments, EPA is guided by 

the principles of the 2005 IPCS guidance on chemical specific adjustment factors. 41 The 

guidance recommends that intra-species factors should be extrapolated from a measure of central 

tendency in the population to a measure in the sensitive population (i.e., to extrapolate from a 

typical human to a sensitive human). This is conceptually consistent with the way EPA applies 

the intra-species uncertainty factor. To base the factor on the difference between the single 

lowest and highest measurements in a given study, as petitioners suggest in this instance, would 

 

40 Eskenazi,B; Huen, K., Marks, A., Harley, K.G., Bradman, A., Boyd Barr, D., Holland, N. (2010) PON1 and 

Neurodevelopment in Children from the CHAMACOS Study Exposed to Organophosphate Pesticides in Utero. 

Environmental Health Perspectives. Vol 118 (12): 1775-1781); Engel,S.M., Wetmur, J., Chen, J., Zhu, C., Boyd 

Barr, D., Canfield, R.L., Wolff, M.S., (2011) Prenatal Exposure to Organophosphates, Paraoxonase 1, and Cognitive 

Development in Childhood Environ Health Perspect 119:1182–1188 (2011). doi:10.1289/ehp.1003183 [Online 21 

April 2011]; Harley KG, Huen K, Schall RA, Holland NT, Bradman A, et al. (2011) Association of 

Organophosphate Pesticide Exposure and Paraoxonase with Birth Outcome in Mexican-American Women. PLoS 

ONE 6(8): e23923. doi:10.1371/journal.pone.0023923. 

41 IPCS (International Programme on Chemical Safety) 2005. Chemical-Specific Adjustment Factors for 

Interspecies Differences and Human Variability: Guidance Document for Use of Data in Dose/ConcentrationResponse Assessment. Harmonization Project Document No. 2. World Health Organization, International 

Programme on Chemical Safety, Geneva, Switzerland. 
12 

likely greatly exaggerate potential intra-species variability. That approach effectively assumes 

that the PoD in an EPA risk assessment will be derived from the least sensitive test subject, 

thereby necessitating the application of an intra-species factor that accounts for the full range of 

sensitivity across a species. Since EPA does not develop its PoDs in this fashion; the approach 

suggested by petitioners is not appropriate. 

In summary, the Agency has carefully considered the issue of PON1 variability and 

determined that data addressing PON1 in isolation are not appropriate for use alone in deriving 

an intra-species uncertainty factor. Further, the derivation of the 164X value advocated by the 

petitioners is based on combining values from humanized mice with human measured values 

with a range from highest to lowest; the Furlong et al. derivation is inappropriate and 

inconsistent with international risk assessment practice.42 Finally, petitioners’ statement that the 

Furlong et al. study supports an intra-species uncertainty factor of at least 150X likely overstates 

potential variability. While EPA does believe that further research in this area may be required, 

in part, because multiple factors most likely impact potential population sensitivity, at this time, 

there is no scientific basis for departing from the standard 10-fold intra-species uncertainty factor 

for extrapolating variability based on PON1. The Agency will continue to monitor the scientific 

literature regarding PON1. At this point in time, however, petitioners’ claims regarding PON1 

would not be a factor in any risk determination the Agency might make to revoke chlorpyrifos 

tolerances. EPA therefore intends to deny this aspect of the petition when it publishes its 

response to the petition in the Federal Register. 

2. Endocrine Disrupting Effects 

a. Petitioners’ claim

Petitioners summarize a number of studies evaluating the effects of chlorpyrifos on the 

endocrine system, asserting that, taken together, the studies “suggest that chlorpyrifos may be an 

endocrine disrupting chemical, capable of interfering with multiple hormones controlling 

reproduction and neurodevelopment.” The petitioners then assert that EPA should not have 

delayed consideration of endocrine effects absent finalization of the Endocrine Disruptor 

Screening Program43 (EDSP) and should have quantitatively incorporated the studies into the 

chlorpyrifos IRED. 

b. Agency Response 

This portion of the petition appears largely to be a complaint about the completeness of 

EPA’s reregistration decision and a request that EPA undertake quantitative incorporation of 

endocrine endpoints into its assessment of chlorpyrifos. The petition does not explain whether 

and how endocrine effects should form the basis of a decision to revoke tolerances. The basis for 

seeking revocation of a tolerance is a showing that the pesticide is not “safe.” Petitioners have 

neither asserted that EPA should revoke tolerances because effects on the endocrine system 

render the tolerances unsafe, nor have petitioners submitted a factual analysis demonstrating that 

aggregate exposure to chlorpyrifos presents an unsafe risk to humans based on effects on the 

 

42 Id. 43 See http://www.epa.gov/endo/
13 

endocrine system. Rather, the petition appears to collect a number of studies suggesting that 

chlorpyrifos may have effects on the endocrine system and that EPA should have considered 

those health impacts at reregistration in a quantitative assessment. 

To the extent that petitioners are seeking tolerance revocation on these grounds, the 

petition fails to provide a sufficient basis for revocation because, in addition to the preceding 

defects, the cited data do not provide quantitative data (i.e. endpoints/PoDs) that indicate 

endocrine effects at doses that are more sensitive than the PoDs currently used in the 

chlorpyrifos risk assessment. While the cited studies provide qualitative information that 

exposure to chlorpyrifos may be associated with effects on the androgen and thyroid hormonal 

pathways, these data alone do not demonstrate that current human exposures from existing 

tolerances are unsafe. The Agency noted similar effects during its evaluation of information 

submitted by People for the Ethical Treatment of Animals (PETA) and the Physicians 

Committee for Responsible Medicine (PCRM) during its review of existing information as part 

of EPA’s EDSP, as discussed below. Based on the review of that data, EPA concluded that the 

effects seen in those studies do not call into question EPA’s prior safety determinations 

supporting the existing tolerances; the data do not indicate a risk warranting regulatory action, 

and the petitioners have provided no specific information to alter this determination. 

Consequently, the petition does not support a conclusion that existing tolerances are 

unsafe due to potential endocrine effects. EPA, therefore, intends to deny this portion of the 

petition when it publishes its response to the petition in the Federal Register. However, because 

the cited literature studies provide qualitative information to screen chlorpyrifos for the potential 

to interact with the estrogen, androgen, and thyroid hormonal pathways, EPA will include them 

in its upcoming weight of evidence evaluation of chlorpyrifos under EPA’s EDSP, as required by 

section 408(p) of the FFDCA. 

As petitioners may be aware, since the filing of the petition, EPA has initiated the 

evaluation of chlorpyrifos under EPA’s EDSP, as required under FFDCA section 408(p). 

On April 15, 2009, a Federal Register notice was published in which chlorpyrifos was 

included in the initial list of chemicals to receive EDSP Tier 1 test orders. The EDSP program is 

a two-tiered screening and testing program; Tier 1 assays and Tier 2 tests. Tier 1 includes 11 

assays in the battery; these data are intended to allow EPA to determine whether certain 

substances (including pesticide active and other ingredients) have the potential to interact with 

the endocrine system and cause an effect in humans or wildlife similar to an effect produced by a 

“naturally occurring estrogen, or other such endocrine effects as the Administrator may 

designate.” The purpose of Tier 2 tests is to identify and establish a quantitative, dose-response 

relationship for any adverse effects that might result from the interactions with the endocrine 

system. 

On November 5, 2009, EPA issued Tier 1 test orders to the registrants of chlorpyrifos, 

requiring a battery of 11 screening assays to identify the potential to interact with the estrogen, 
14 

androgen, or thyroid hormonal systems.44 On February 13, 2010, EPA received the 90-day 

responses to the test orders. In the initial response, the test order recipients agreed to conduct 9 

of the 11 assays that comprise the EDSP Tier 1 screening battery. The test order recipients also 

sought to rely on existing data for two of the 11 assays, the male and female pubertal assays. The 

Agency also received a submission from PETA and PCRM that cited existing studies that they 

claimed adequately fulfill the requirements of the EDSP Tier1 battery for chlorpyrifos. 

 On October 20, 2010, following the review of the Other Scientifically Relevant 

Information (OSRI) that had been submitted, EPA determined that the male pubertal assay test 

order was satisfied based on the OSRI submitted by PETA/PCRM; this conclusion was based on 

an interpretation that the data demonstrated potential interaction with the androgen and thyroid 

hormonal pathways.45 For the female pubertal assay, however, EPA determined that the assay 

was still necessary because of deficiencies and unanswered questions in the studies cited in the 

OSRI submissions. The study deficiencies included the lack of thyroid weights and thyroid 

hormone measurements. In addition, organ weights and histopathology data were obtained in 

adult animals, whereas in the Tier 1 female pubertal assay, this data is obtained in pubertal 

animals. 

The test order recipients disagreed with the Agency’s interpretation that the OSRI 

submitted by PETA/PCRM demonstrated potential interaction with the androgen and thyroid 

hormonal pathways. Because the test order recipients disagreed with the Agency’s interpretation 

of the data cited for the Male Pubertal Assay, they elected to conduct the full Tier 1 battery of 

assays. The Agency has received all 11 Tier 1 screening assays and is in the data review process. 

EPA intends to review these chlorpyrifos data as part of its larger process for reviewing all of the 

Tier 1 data submitted on List 1 EDSP chemicals. 

Consistent with the recommendation of the joint Scientific Advisory Board and FIFRA 

SAP in 1999 (EPA-SAB-EC-00-013, July 1999), the Agency plans to conduct a mid-course 

review of the functionality of each assay and the battery as a whole. These performance 

evaluations of the Tier 1 battery will be conducted on an adequate sample of chemicals and it is 

further anticipated that these Tier 1 performance review results will be submitted for external 

scientific peer review by the FIFRA SAP in fiscal year 2013. Specifically, EPA intends to first 

review the data from each individual assay for several chemicals to ensure that EPA consistently 

interprets the measurements for particular endpoints in that assay; e.g., EPA will review the 

thyroid weight measurements reported in the male pubertal assays from a number of chemicals to 

ensure that the Agency reaches consistent conclusions as to the significance of the reported 

results. After that process has been completed, EPA will evaluate each chemical’s response 

across the battery of 11 assays to determine whether there is evidence of interaction with the 

estrogen, androgen, and/or thyroid hormone systems. 

EPA believes that the results from the entire battery of Tier 1 screening and Tier 2 testing 

under the EDSP program are necessary to make the statutory determination of whether a 

 

44 See http://www.epa.gov/endo/pubs/toresources/index.htm for information related to the status of EDSP test 

orders/DCIs, status of EDSP OSRI: order recipient submissions and EPA responses, and other EDSP assay 

information. 

45 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0634-0159. 
15 

substance may have an effect similar to an effect produced by a naturally occurring hormone (FR 

Vol, 63, No. 248/Monday December 28, 1998). In other words, a positive result in the Tier 1 

screening assays would not be sufficient to make the determination of whether chlorpyrifos 

interacted with the endocrine system. The citations included in the petition referred to as 

evidence that chlorpyrifos may affect estrogen, androgen, and thyroid hormonal pathways do not 

establish quantitative, dose-response relationships for potential endocrine effects, which is the 

purpose of Tier 2 testing. 

The information cited in the petition will be considered along with all other information 

submitted to the Agency by either the test order recipient or the public, including the information 

already submitted by the petitioners, using a weight-of-evidence (WoE) approach consistent with 

the Agency’s September 14, 2011 EDSP WoE guidance.46 Based on this WoE assessment, EPA 

will determine whether chlorpyrifos has the potential to interact with hormone pathways and, if 

so, whether any Tier 2 or other, more targeted testing, is required to confirm interaction with 

specific hormone systems and to characterize any potential effects identified through Tier 1 

screening, and to establish the dose response relationships for adverse effects necessary to 

conduct a quantitative risk assessment. 

In summary, EPA believes that evaluating all of the evidence with respect to 

chlorpyrifos’s potential for endocrine disruption through the Agency’s standard EDSP process, 

as explained above, is the appropriate approach to address petitioners’ request that EPA 

incorporate endocrine effects into its risk assessment for chlorpyrifos. This is a transparent and 

scientifically sound process that has been the subject of external peer review47 and is designed to 

ensure that all data are appropriately considered. By relying on this robust scientific process, 

EPA believes that it will ultimately reach a final, scientifically credible determination more 

efficiently than if EPA were to conduct repeated reviews of the data in piecemeal and without 

context. 

3. Cancer Risks 

a. Petitioners’ claim 

Petitioners claim that the Agency “ignored” a December 2004 National Institutes of 

Health Agricultural Health Study (AHS) by Lee et al. (2004) 48 that evaluated the association 

between chlorpyrifos and lung cancer incidence.49 The petition summarizes the results of the 

AHS study, stating that the incidence of lung cancer has a statistically significant association 

with chlorpyrifos exposure. The petition then asserts that these data are highly relevant and 

 

46 U.S. EPA (2011), Endocrine Disruptor Screening Program: Weight-of-Evidence: Evaluating Results of EDSP 

Tier 1 Screening to identify the Need for Tier 2 Testing. Available at 

http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2010-0877-0021 

47 See Scientific Advisory Panel, 2008 SAP Meetings, March 25-28, 2008: Review the Endocrine Disruptor 

Screening Program (EDSP) Proposed Tier-1 Screening Battery. Available at 

http://www.epa.gov/scipoly/sap/meetings/2008/032508_mtg.htm

48 Lee WJ, Blair A, Hoppin JA, Lubin JH, Rusiecki JA, Sandler DP, Dosemeci M, Alavanja MC. (2004) Cancer 

incidence among pesticide applicators exposed to chlorpyrifos in the Agricultural Health Study. J Natl Cancer Inst, 

96(23), 1781-1789. (hereinafter Lee et al. 2004). 

49 Petition at 10 
16 

therefore should have been referenced in the final aggregate assessment for chlorpyrifos or the 

OP CRA. Petitioners do not otherwise explain whether and how these data support revocation of 

tolerances or cancellation of pesticide registrations. 

b. Agency Response 

As explained in the previous section, the basis for seeking revocation of a tolerance is a 

showing that the pesticide is not “safe.” Claiming that EPA failed to reference certain data in its 

risk assessment regarding carcinogenicity does not amount to illustrating that the tolerances are 

unsafe. To show a lack of safety, petitioners would have to present some fact-based argument 

demonstrating that aggregate exposure to chlorpyrifos poses an unsafe carcinogenic risk. 

Petitioners have not presented such an analysis. Accordingly, when EPA publishes its response 

to the petition in the Federal Register, EPA intends to deny the petitioners’ request to revoke 

chlorpyrifos tolerances or cancel chlorpyrifos registrations to the extent that request relies on 

claims pertaining to carcinogenicity. 

Despite the inadequacy of petitioners’ cancer claims, in the course of the Agency’s 

review of chlorpyrifos, EPA has examined the Lee et al. study cited by petitioners,50 among other 

lines of evidence. EPA has concluded that the Lee et al. investigation does not alter the Agency's 

weight of evidence determination concerning chlorpyrifos’ carcinogenic potential, and therefore 

does not alter the Agency's current cancer classification for chlorpyrifos. Specifically, the 

Agency does not believe this evidence raises sufficient grounds for concern regarding 

chlorpyrifos that EPA should consider initiating action based upon this information that might 

lead to revocation of the chlorpyrifos tolerances or cancellation of the chlorpyrifos registrations. 

The Agency was aware of the December 2004 study cited by petitioners. While Lee et al. 

observed a possible association between chlorpyrifos use and the incidence of lung cancer, the 

authors also stressed that further evaluation was necessary before concluding the association was 

causal in nature.51 Additional evaluation is necessary because of possible alternative 

explanations for the Lee et al. study, which include unmeasured confounding factors or 

confounding factors not fully accounted for in the analysis, and possible false positive results due 

to the performance of multiple statistical tests. 

EPA has been a collaborating agency with the AHS since 1993, and continues to closely 

monitor the AHS literature. The Agency is working closely with the AHS researchers to clearly 

understand the results of their research efforts to ensure the Agency appropriately interprets these 

data as future studies are published. Between 2003 and 2009 there have been six nested casecontrol analyses within the AHS which evaluated the use of a number of agricultural pesticides, 

including chlorpyrifos, in association with specific anatomical cancer sites, in addition to the 

previously published cohort study52 cited by the petitioners. As noted below, both the Agency 

and Health Canada have comprehensively reviewed these data. Further, the Agency has 

 

50 U.S. EPA (2011). Christenson Memorandum “Chlorpyrifos Carcinogenicity: Review of Evidence from the U.S. 

Agricultural Health Study (AHS) Epidemiologic Evaluations 2003-2009. (hereinafter Christenson 2011). 51 Lee et al. 2004 at 1788. 

52 Lee et al 2004. 
17 

proposed a draft framework53 to consider epidemiologic information in the risk assessment 

process, and additionally utilized AHS data in a case study illustrating the similarities and 

differences in exposure assessment methodology between epidemiologic research and regulatory 

risk assessment. 

In accordance with the Agency’s 2005 Guideline for Cancer Risk Assessment,54

chlorpyrifos is classified as “Not Likely to be Carcinogenic to Humans” based on the lack of 

evidence of carcinogenicity in male or female mice and male or female rats. In chronic toxicity/ 

carcinogenicity studies, animals received chlorpyrifos in their feed every day of their lives (78 

weeks for mice and 104 weeks for rats) at doses thousands of times greater than any anticipated 

exposure to humans from authorized uses. There was no evidence of cancer in the experimental 

animal studies. Additionally, available evidence from in vivo and in vitro assays did not support 

a mutagenic or genotoxic potential of chlorpyrifos. 

Recently, the Agency conducted its own review of the six nested case-control analyses 

and one cohort study within the AHS concerning the carcinogenic potential of chlorpyrifos.55 

EPA concluded with respect to the AHS lung cancer results that the findings are useful for 

generating hypotheses, but require confirmation in future studies. This conclusion is consistent 

with that of researchers from Health Canada. Specifically, Weichenthal et al. (2010)56 recently 

published a review article in Environmental Health Perspectives on pesticide exposure and 

cancer incidence in the AHS cohort. Their review of these same studies concluded that the 

weight of experimental toxicological evidence does not suggest that chlorpyrifos is carcinogenic, 

and that epidemiologic results currently available from the AHS are inconsistent, lack 

replication, and lack a coherent biologically plausible carcinogenic mode of action. The authors 

did note positive exposure-response associations for chlorpyrifos and lung cancer in two separate 

evaluations. The Agency will continue to review additional AHS data as well as other 

epidemiologic evaluations during the development of the HHRA. 

In summary, while there is initial suggestive epidemiological evidence of an association 

between chlorpyrifos and lung cancer to only form a hypothesis as to a carcinogenic mode of 

action, additional research (including follow-up AHS research) is needed to test the hypothesis. 

Consequently, at this time it is reasonable to conclude chlorpyrifos is not a carcinogen in view of 

the lack of carcinogenicity in the rodent bioassays and the lack of a genotoxic or mutagenic 

potential. The Agency concludes that existing epidemiological data (including Lee et al.) do not 

change the current weight of the evidence conclusions. The Agency continues to believe there is 

not a sufficient basis to alter its assessment of chlorpyrifos as not likely to be carcinogenic to 

humans when multiple lines of evidence are considered (e.g., epidemiology findings, rodent 

bioassay, genotoxicity); therefore, chlorpyrifos cancer risk would not be a factor in any potential 

Agency risk determination to revoke tolerances for chlorpyrifos. 

 

53 U.S. EPA Presentation to the FIFRA Science Advisory Panel, February 2010. Avaliable at 

http://www.epa.gov/scipoly/sap/meetings/2010/020210meeting.html#materials. 54 U.S. EPA (2005). Guidelines for Carcinogen Risk Assessment. Available at 

http://www.epa.gov/raf/publications/pdfs/CANCER_GUIDELINES_FINAL_3-25-05.PDF. 55 Christenson 2011. 

56 Weichenthal S, Moase C, Chan P (2010). A review of pesticide exposure and cancer incidence in the agricultural 

health study cohort. Cien Saude Colet. 2012 Jan;17(1):255-70. PubMed PMID: 22218559. 
18 

4. CRA misrepresents risks, failed to apply FQPA10X Safety Factor 

a. Petitioners’ claim

Petitioners assert that EPA relied on limited data and inaccurate interpretations of data to 

support its decision to remove the FQPA safety factor in the CRA.57 Specifically, the petitioners 

challenge the Agency’s use of data from a paper by Zheng et al. (2000)58 claiming that, in 

contrast to the Agency’s analysis of the study data, the data does show an obvious difference 

between juvenile and adult responses to chlorpyrifos.59 Petitioners conclude by asserting that the 

Zheng et al. study supports using a 10X safety factor for chlorpyrifos in the CRA. 

b. Agency Response 

Petitioners’ assertions do not provide a sufficient basis for revoking chlorpyrifos 

tolerances. As explained previously, the ground for seeking revocation of a tolerance is a 

showing that the pesticide is not “safe.” The petitioners’ claim that the data EPA relied upon 

support a different FQPA safety factor for chlorpyrifos in the CRA does not amount to a showing 

that chlorpyrifos tolerances are unsafe. To show a lack of safety, petitioners would have to 

present a factual analysis demonstrating that the lack of a 10X safety factor in the CRA for 

chlorpyrifos poses unsafe cumulative exposures to the OP pesticides. Petitioners have not made 

such a showing. For this reason, when EPA publishes its response to the petition in the Federal 

Register, EPA intends to deny the petitioners’ request to revoke chlorpyrifos tolerances or cancel 

chlorpyrifos registrations to the extent that request relies on claims pertaining to EPA’s failure to 

provide a 10X safety factor in the OP CRA based on the results of the Zheng et al. study. 

Despite the inadequacy of petitioners’ FQPA safety factor claims, EPA has examined the 

evidence cited by petitioners for the purpose of evaluating whether the evidence raises sufficient 

grounds for concern regarding chlorpyrifos that EPA should consider initiating action that might 

lead to revocation of the chlorpyrifos tolerances. 

In general, when the Agency conducts a cumulative assessment, the scope of cumulative 

risk is limited to the common mechanism endpoint -- which in this case is cholinesterase 

inhibition, the primary toxicity mode of action and the most sensitive, quantifiable endpoint for 

the OP pesticides. As such, for the OP CRA, experimental toxicology data on AChE inhibition 

are used for developing relative potency estimates, PoDs, and informing the FQPA safety factor. 

EPA has relied on brain AChE data from adult female rats dosed for 21 days or longer for 

estimating relative potency and PoDs. At approximately three weeks of oral exposure to OP 

pesticides, AChE inhibition reaches steady state in the adult rat such that continued dosing does 

not result in increased inhibition. This timeframe of toxicity (21-days and longer) was selected 

as there was high confidence in the potency estimates derived from the steady state toxicology 

studies due to the stability of the AChE inhibition. 

 

57 Petition at 16. 

58 Zheng Q, Olivier K, Won YK, Pope CN. 2000. Comparative cholinergic neurotoxicity of oral chlorpyrifos 

exposures in preweaning and adult rats. Toxicological Sciences, 55(1): 124-132. 

59 Petition at 14. 
19 

The Agency’s 2006 OP CRA contains EPA’s complete FQPA safety factor analysis,60

which involved consideration of pre-natal and post-natal experimental toxicology studies, in 

addition to exposure information. In the OP CRA, pre-natal exposure AChE studies in rats show 

that the fetus is no more sensitive than the dam to AChE inhibition and the fetus is often less 

sensitive than the dam. Thus, evaluating the potential for increased toxicity of juveniles from 

post-natal exposure was a key component in determining the magnitude of the FQPA safety 

factors in the OP CRA. Furthermore, because characteristics of children are directly accounted 

for in the cumulative exposure assessment, the Agency’s methods are not expected to 

underestimate exposure to OP pesticides. 

In the CRA, each OP pesticide was assigned a 10X FQPA safety factor unless chemicalspecific AChE data on young animals were available to generate a data derived safety factor. To 

best match the relative potency factor and PODs based on repeated dosing, the Agency used 

repeated dosing data in juveniles for developing the FQPA safety factors. For chlorpyrifos, at 

the time of the 2006 OP CRA, the only such data available were from the Zheng et al. literature 

study. 

The petitioners are correct that Dr. Carey Pope of Oklahoma State University, who is also 

a member of the FIFRA SAP, provided the Agency with the raw data from the Zheng et al. 

study. These raw data were used to develop the plot in the 2006 OP CRA which was reproduced 

in the petition. Petitioners accurately note that for other OP pesticides a benchmark dose (BMD) 

modeling approach was used and that no BMD values were reported for chlorpyrifos. In 

determining the FQPA safety factor, petitioners claim that the Agency misinterpreted the brain 

AChE data from Zheng et al. 

As shown in the plot reproduced on page 15 of the petition, the dose-response data in the 

Zheng et al. study are variable and lack a monotonic shape at the low dose end of the dose 

response curve. The Agency acknowledges that at the high dose, the pups appear to be more 

sensitive. However, at the low dose end of the response curve, relevant for human exposures 

and, thus, the cumulative risk assessment (i.e., at or near the 10% inhibition level), little to no 

difference is observed. Therefore, despite the lack of BMD estimates for the Zheng et al. study, 

in 2006 the Agency was confident in the value used. Since that time, the Agency attempted 

BMD modeling of the Zheng et al. data as part of the 2011 preliminary chlorpyrifos HHRA61

which yielded low confidence results due to the variability in the data 

Dow AgroSciences recently submitted a new comparative cholinesterase study (CCA) for 

chlorpyrifos. CCA studies are specially designed studies to compare the dose-response 

relationship in juvenile and adult rats. This CCA study includes two components: 1) acute, 

single dosing in post-natal day (PND) 11 and young adult rats and 2) 11-days of repeating dosing 

in rat pups from PND11-21 and 11-days of repeated dosing in adult rats. The CCA study for 

chlorpyrifos is considered by EPA to be high quality and well-designed. The preliminary risk 

assessment for chlorpyrifos’ reports BMD estimates from this CCA study. Specifically for the 

 

60 Available at http://epa.gov/pesticides/cumulative/2006-op/op_cra_main.pdf. 61 U.S. EPA (2011). Chlorpyrifos: Preliminary Human Health Risk Assessment for Registration. Available in 

docket number EPA-HQ-OPP-2008-0850, http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2008-

0850-0025. 
20 

repeated dosing portion of the study, the BMD10s of 0.80 (0.69 BMDL10) and 1.0 (0.95 BMDL10) 

mg/kg/day respectively for female pups and adults results support the FQPA safety factor of 1X 

used in the 2006 OP CRA. Therefore, the Agency remains confident in the FQPA safety factor 

of 1X used in the cumulative risk assessment for chlorpyrifos. As such, petitioners’ claims 

regarding the OP CRA and FQPA safety factor, at this time would not be a factor in a 

determination by the Agency to revoke tolerances for chlorpyrifos. 

5. Over-reliance on registrant data 

a. Petitioners’ Claim

Petitioners assert that EPA “cherry picked” data, “ignoring robust, peer-reviewed data in 

favor of weak, industry-sponsored data to determine that chlorpyrifos could be re-registered and 

food tolerances be retained.”62 As such, the Agency’s reassessment decision is not scientifically 

defensible.63

b. Agency Response 

This portion of the petition does not purport to be an independent basis for revoking 

chlorpyrifos tolerances or cancelling chlorpyrifos registrations. Rather, this claim appears to 

underlie petitioners’ arguments in other sections of the petition. While petitioners claim that 

EPA ignored robust, peer-reviewed data in favor of weak, industry-sponsored data for the 

reregistration of chlorpyrifos, petitioners do not cite to any studies other than those used to 

support their other claims. In general, petitioners did not provide any studies in their petition that 

EPA failed to evaluate. Since the specific studies cited by petitioners are not associated with this 

claim, but rather their other claims, EPA’s response to the specific studies are, therefore, 

addressed in its responses to petitioners’ other claims. However, EPA explains below why, as a 

general matter, the Agency does not believe it has “over-relied” on registrant data in evaluating 

the risks of chlorpyrifos or other pesticides. 

In spite of petitioners’ claim, the Agency does not ignore robust, peer-reviewed data in 

favor of industry-sponsored data. Further, EPA has a very public and well-documented set of 

procedures that it applies to the use and significance accorded all data utilized to inform risk 

management decisions. Registrant generated data, in response to FIFRA and FFDCA 

requirements, are conducted and evaluated in accordance with a series of internationally 

harmonized and scientifically peer-reviewed study protocols designed to maintain a high 

standard of scientific quality and reproducibility.64 

Additionally, to further inform the Agency’s risk assessment, EPA is committed to the 

consideration of other sources of information such as data identified in the open, peer-reviewed 

literature and information submitted by the public as part of the regulatory evaluation of a 

 

62 Petition at 16. 

63 Id. 64 See http://www.epa.gov/opp00001/science/guidelines.htm for information on EPA’s Harmonized Test Guidelines 

and international efforts at harmonization. 
21 

pesticide. An important issue, when evaluating any study, is its scientific soundness and quality, 

and thus, the level of confidence in the study findings to contribute to the risk assessment. 

The literature was searched, fully considered, and provided additional information on, 

chlorpyrifos mode of action, pharmacokinetics, epidemiology, neurobehavioral effects in 

laboratory animals, and age dependent sensitivity to cholinesterase inhibition. This information 

is discussed in the 2008 chlorpyrifos SAP paper and the chlorpyrifos 2011 preliminary HHRA. 

 Therefore, by evaluating registrant data in accordance with internationally harmonized 

and scientifically peer-reviewed study protocols, undertaking thorough open literature searches, 

and considering information provided by the public, the Agency is confident that its assessment 

for chlorpyrifos was reasonably based upon the best available science at the time of the 

assessment. Previous sections of this response to petitioners’ claims regarding the Agency’s 

inadequate use of various data only further highlights and supports the scientifically defensible 

results of the Agency’s assessment. Petitioners’ claim that the Agency overly relies on registrant 

data is unfounded and not supported by the record and as such, it would form no basis of the 

Agency’s decision to revoke chlorpyrifos tolerances or cancel chlorpyrifos registrations. 

 6. Export Hazard 

a. Petitioners’ claim

Petitioners assert that EPA must ban chlorpyrifos and cancel all tolerances because, 

otherwise, chlorpyrifos will continue to be used unsafely by workers, including children, in other 

countries who may not utilize worker protection equipment required for use in the U.S.65 In 

addition, petitioners assert that continued chlorpyrifos use internationally presents a health 

hazard from contaminated food re-entering the United States.66 

b. Agency Response. 

The Agency takes very seriously its leadership role and commitment to international 

efforts to promote the safe use of pesticides. EPA's principal goal in international pesticide 

activities is to improve the protection of public health and the environment throughout the 

world.67 Under FIFRA and FFDCA, however, EPA’s primary focus in regulating pesticides is to 

address risk from domestic use of pesticides and from pesticide residues on imported food. It is 

far from clear that EPA has any authority under FIFRA to address the risks to foreign workers 

 

65 Petition at 21. 

66 Id. 67 EPA actively participates in Codex, which is a joint food standards program of the United Nations Food and 

Agriculture Organization (FAO) and the World Health Organization (WHO). Codex develops international food 

safety and quality standards, including Maximum Residue Limits (MRLs) for pesticides. EPA contributes technical 

expertise to the development of these standards and related policies. Additional information can be found at 

http://www.codexalimentarius.net/web/index_en.jsp. EPA is also active in the Organization for Economic Cooperation and Development (OECD) Working Group on Pesticides. The objective of the OECD Pesticide Program 

is to help governments co-operate in assessing and reducing the risks of agricultural pesticides. Additional 

information on the OECD pesticide program can be found at 

http://www.oecd.org/document/34/0,3746,en_2649_37465_48447010_1_1_1_37465,00.html. 

23 

Additional References 

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Forms Of Human Serum Paraoxonase/Arylesterase: Glutamine Or Arginine At Position 191, For 

The Respective A Or B Allozymes. Am J Hum Genet. 52(3):598-608. 

Blatter Garin, M. C., James, R. W., Dussoix, P., Blanche, H., Passa, P., Froguel, P, Ruiz, J. 

(1997). Paraoxonase Polymorphism Met-Leu54 is Associated With Modified Serum 

Concentrations of the Enzyme. J. Clin Invest. 99: 62-66. 

Cole, T. B., Walter, B. J., Shih, D. M., Tward, A. D. Lusis, A. J, Timchalk, C. Richter, R. J., 

Costa, L. G. and Furlong, C. E. (2005). Toxicity Of Chlorpyrifos And Chlorpyrifos Oxon In A 

Transgenic Mouse Model Of The Human Paraoxonase (PON1) Q192R Polymorphism. 

Pharmacogenetics and Genomics 15:589–598. 

Humbert, R., Adler, D. A., Disteche, C. M., Hassett, C., Omiecinski, C. J., Furlong, C. E. (1993). 

The Molecular Basis Of The Human Serum Paraoxonase Activity Polymorphism. Nat Genet. 

3(1):73-6. 

Jarvik, G. P., Hatsukami, T. S., Carlson, C., Richter, R. J., Jampsa, R., Brophy, V. H., Margolin, 

S., Rieder, M., Nickerson, D., Schellenberg, G.D., Heagerty, P. J., Furlong, C. E. (2003). 

Paraoxonase Activity, But Not Haplotype Utilizing The Linkage Disequilibrium Structure, 

Predicts Vascular Disease. Arterioscler Thromb Vasc Biol. 23(8):1465-71. 

Mackness, M. I., and Walker, C. H. (1988). Multiple Forms Of Sheep Serum A-Esterase Activity 

Associated With The High-Density Lipoprotein. Biochem J. 250(2):539-45. 

Renwick, A. G. (1993). Data-Derived Safety Factors for the Evaluation of Food Additives and 

Environmental Contaminants. Food Addit. Contam. 10, 275–305. 

Renwick, A. G., and Lazarus, N. R. (1998). Human Variability And Noncancer Risk 

Assessment--An Analysis Of The Default Uncertainty Factor. Regul Toxicol Pharmacol. (1 Pt 1, 

2): 3-20 

US EPA. 1999. US Environmental Protection Agency. Policy on a Common Mechanism of 

Action: The Organophosphate Pesticides. Federal Register 64(24):5795-5799. February 5.