2 1. EPA ignored genetic evidence of vulnerable populations

2. EPA needlessly delayed a decision rega rding endocrine disrupting effects

3. EPA ignored data regarding cancer risks

4. EPA’s CRA misrepresented risks, fail ed to apply FQPA 10X safety factor 3

5. EPA over-relied on registrant data

6. EPA failed to properly address the e xporting hazard from chlorpyrifos

7. EPA failed to quantitatively in corporate data demonstrati ng long-lasting effects from early life exposure to chlorpyrifos in children

8. EPA disregarded data demonstrat ing that there is no evidence of a safe level of exposure during pre-birth and early life stages

9. EPA failed to cite or quantit atively incorporate studies a nd clinical reports suggesting potential adverse effects below 10% cholinesterase inhibition

10. EPA failed to incorporate i nhalation 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 safe ty factor; over-reliance on registrant data; and exporting hazard. EPA’s response to three of petitioners’ remain ing four claims -- that EPA failed to quantitatively in corporate data exhibiting long-lastin g effects from early life exposure to chlorpyrifos in children; that EPA disregarded da ta demonstrating that th ere 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 a dverse effects below 10% cholinesterase inhibition -- involve highly complex assessments, using precedent setting risk assessment methodologies. For this reason, cons istent with EPA’s external scientific peer review policy, the Agency sought advice on these i ssues 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 remain ing claim -- that EPA failed to incorporate inhalation routes of exposure -- EPA is today releasing its “Eva luation 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 wa s presented in the preliminary human health risk assessment (HHRA) released in July 2011. In co nnection with this spra y drift assessment, the chlorpyrifos registrants have agreed to implemen t 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 mitiga tion action does not take into account potential exposures from volatilization following chlorpyrif os applications. That work is ongoing. Further, the spray drift risk a ssessment 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 requir ements regarding the additional safety margin for infants and children in section 408(b)(2)(C) are referred to throughout this respon se as the “FQPA 10X safety factor” or simp ly the “FQPA safety factor. Due to Congress’ focus on both pre- and po st-natal toxicity, EPA has inte rpreted 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 report 5 , dated July 11, 2012. EPA will carefu lly review and consider the SAP’s recommendations in developing the Agency’s re sponse to the remaining petition issues while also informing the final human health risk asse ssment for the statutor ily mandated registration review program. Following EPA's complete writt en 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 registratio n 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 dri nking water. It is important to note, however, that EPA may take regulatory action at any time if and when it de termines that existing to lerances are unsafe or that chlorpyrifos presents unreasonabl e adverse effects on the environment.

The first section of this response provid es the applicable st atutory and regulatory background. The second section di scusses this petition in the context of th e legal framework of

FIFRA and FFDCA. The third sect ion discusses the regulatory background for chlorpyrifos. The fourth section contains EPA’s response to each of the six issues iden tified 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 pest icide 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 toleran ce, a food containing a pesticide residue is

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

commerce. 7 Monitoring and enforcement of pesticid e tolerances are carri ed out by the U.S. Food and Drug Administration and the U.S. De partment of Agriculture. Section 408 was substantially rewritten by the Food Quality Protection Act of 1996 (FQPA), which added the provisions discussed below establ ishing a detailed safety standard for pesticides, additional protections for infants and ch ildren, and the estrogenic s ubstances 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, FI FRA requires the approval of pesticides prior to their sale and distribution, 10 and establishes a re gistration regime for regulating the use of pesticides. FIFRA regulates pesticide use in conjunction with its registration scheme by requiring EPA review and approval of pe sticide labels and spec ifying 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 requi ring that the safety st andard under the FFDCA

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

5 Available at http://www.regulations.gov/#! documentDetail;D=EPA-H Q-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 coordina te, to the extent practicable,

revocations of tolerances with pesticide cancellations under FIFRA. 13

In addressing the review of petitions, howev er, Congress has expressly provided that any issue that can be raised through the FFDCA revi ew process can only be reviewed through that

process. 14 Accordingly, to the extent a petition to revoke tolerances a nd cancel registrations

raises issues relevant to the establishment or revocation of tolerances, EPA’s response to those issues may be challenged only through the admi nistrative and judicial review procedures provided in section 408 of th e 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 petiti on relate to EPA's establishment of tolerances under the FFDCA. For this reason, as explai ned in section I, the FFDCA directs that

consideration of thes e 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 th e Federal Register for th e five issues addressed in this response that are subject to FFDCA revi ew 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 wi sh to begin the objections process on today’s partial response, EPA will publish a formal deni al order for those claims. As explained previously, EPA intends to address, in writing, the remaining issues ra ised 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 peti tion issues immediately following the December 2012 response.

While petitioners have raised a number of issu es related to the assessment of the toxicity of chlorpyrifos, the petition did not address in any detail, dietar y exposure to chlorpyrifos that must be taken into account in determining whethe r tolerances are safe. Reassessing the exposure to chlorpyrifos is one of the issues EPA intends to address in the regi stration review assessment of the chemical, which is curren tly underway. It is possible th at if EPA concludes that the toxicity profile of chlo rpyrifos needs to be modified base d upon this reassessment, the final decision on the petition would need to wait for th e conclusion of the chlorpyrifos exposure reassessment under the registration review progr am. The registration review assessment will

include consideration of issues not raised in the petition, includ ing human dietary exposures from drinking water. It is important to note, however, that EPA may ta ke 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. Johnso n, 461 F.3d 164, 176 (2d Cir. 2006).5 if and when it determines that existing toleran ces 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 peti tion 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 petiti on 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 request s must be filed within 60 days. 19
The statute provides that EPA sha ll ‘‘hold a public evidentiary hear ing if and to the extent the Administrator determines that such a public he aring 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 wher e it is shown that there is ‘‘a genuine and substantial issue of fact,’’ the requestor has identified evidence ‘‘which, if establis hed, resolve one or more of such issues in favor of the requestor,’’ and the issu e 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 d ecision and not just repeat the allegations in its petition. 22 EPA’s final order on the objections is subject to judi cial 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 clai m that “unless chlorpyrifos is banned, and all tolerances cancelled [sic], chlor pyrifos 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 regard ing 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 Sec tion 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 cancellati on 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 eith er denying their petition or by initiating and completing the cancellation process under FIFRA.

EPA considers this portion of the response to NRDC’s petitio n 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. Becau se, as explained below, EPA is today denying petitioners’ request to cancel on the basis of the export hazard issu e, this letter will constitute a final Agency action as it relates to that specific issue. As noted, the rema ining issues are subject to review as provided in section 408 of the FFDCA.

III. Background

In 2000, the chlorpyrifos techni cal registrants entered into an agreement with the Agency regarding the use of chlorpyrif os 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 IR ED 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 e ndpoint, acetylcholinesterase (A ChE) inhibition. Specifically,

the members of this class share the ability to bind to and phosphorylate the enzyme AChE in both the central (brain) and peri pheral 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 e ligibility decisions (RED s) for individual OP pesticides, including chlorpyrifos, were consider ed complete. OP IREDs, therefore, were considered completed REDs.

In September 2007, EPA received NRDC a nd PANNA’s joint petition to revoke all tolerances and cancel all regist rations for chlorpyrifos. The petition largely challenged the conclusions of the Agency’s IRED and 2006 OP CRA.

Although EPA completed reregistration and tole rance reassessment for the OP pesticides in 2006, the Agency made the decision to move ch lorpyrifos and other OP pesticides forward in

the re-evaluation schedule so that they began registrati on review in 2008 and 2009. The chlorpyrifos registration review docket opened in 2009.

In connection with its ongoing re-evaluation of chlorpyrif os 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 e ffects of chlorpyrifos to provid e a preliminary review of the scientific literature on experime ntal toxicology and epidemiology st udies available at that time. Specifically, the focus was on studies that evalua ted the effects of chlorpyrifos on infants and

children from in utero and/or post-natal exposures and on studies that eval uated population variability with respect to response to para xonase (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 epid emiological studies have utility for risk7 characterization, but not as the pr incipal basis for establishing the point of departure (PoD), in part due to uncertainty in at tributing observed adverse neurod evelopmental 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 expos ure assessment was on methods for predicting emissions from treated fields in lieu of having ac tual field volatilization studies as well as how

such information should be considered in exposure assessment. With regard to hazard evaluations, the impact on inha lation 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 resu lting from field volatilization of conventional pesticides. The procedures, refi ned in part from the SAP’s feedback, will inform the Agency’s analysis as it considers chlorpyr ifos 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 re view the Agency’s draft “Framework for Incorporating Human Epidemiologic & Incide nt Data in Health Risk Assessment,” 27 which provides the conceptual foundation for evaluating multiple lines of scient ific evidence in a

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

framework 28 and its use of the modified Bradford Hill Criteria 29 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 Mee ting 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/1203 09meetingminutes.pdf

27 U.S. EPA (2010). Transmittal of Meeting Minuets of th e 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 Muta genic Mode of Action for Carcinogenicity: Using EPA’s 2005 Cancer Guidelines and Supplemental Guidance fo r 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 Asse ssment, 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.PDF8 In July 2011, the Agency released the pr eliminary HHRA for chlorpyrifos for public comment. The comment period officially clos ed on October 6, 2011. The Agency received 48 unique comments totaling over 1000 pages, wh ich included a number of significant study citations. The Agency continues to work on revi ewing the public comments and studies cited to further inform the final HHRA for chlorpyrifos.

Since the 2008 SAP on chlorpyrifos, and in pa rt due to the SAP’s feedback, the Agency has performed further analyses on the existing and new epidemio logy studies with mothers and children, available biomonitoring data, and experi mental toxicology studies evaluating proposed adverse outcome pathways in th e 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 cons ideration of adverse outcome pathway framework analyses, exposure, human epidemiology, and biomonitoring da ta). 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 inte grating the epidemiology studies wi th 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 an alyses 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 variabil ity) for chlorpyrifos in both its aggregate and

cumulative assessments. 30 They assert that certain relevant , robust data, specifically the Furlong et al. (2006) study 31 that addresses intra-species variability in the behavior of the detoxifying enzyme PON1, indicates that the Agency should have applied an intra-specie s safety factor “of at least 150X in the aggregate and cumulative as sessments” rather than the 10X factor EPA applied. 32 Petitioners conclude by noting that applyi ng an intra-species fact or of 100X or higher would require setting tolerances below the leve l of detection, which therefore should compel EPA to revoke all chlorp yrifos tolerances.

30 Petition 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 setti ng the intra-species uncertainty f actor 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 addi tion, EPA believes the methodology utilized in the Furlong et al. study to measure intra-species vari ability – 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 practi ces. Further, EPA believes that petitioners’ assertion that the Furlong et al. study supports an intra-species uncer tainty 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 in tra-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 petitione rs’ 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 popu lations 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. Speci fically, PON1 is an A-esterase which can metabolize chlorpyrifos oxon wit hout inactivating the enzyme. 33 Indeed, as part of the 2008SAP, EPA performed a literature review of PON1 and its possible use in informing the intraspecies (i.e., within human variab ility) uncertainty fact or. This literature review can be found in the draft Appendix E: Data Derived Extrapolatio n 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 P ON1 status with health outcomes following OP pesticide exposure in adults and children (Holland et al., 2006 35 ; 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 Characteriza tion. 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., Brad man, 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 Neona tes. Environmental Health Perspective 111, 11:1403-910 EPA believes that focusing on PON1 variability in isolation from other metabolic action is not an appropriate approach for devel oping a data-driven uncertainty factor. The Agency solicited

feedback from the SAP on the utili ty of the PON1 data, by itself, for use in risk assessment; the SAP was similarly not supportive of using such da ta 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 fact or 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 predic t vulnerability because the overall level of enzyme activity is ultimately what determines detoxifica tion potential from that pathway; thus, it is better to us e PON1 status because it provides information regarding PON1 genotype and activity. Some of the data from laboratory animal studies in PON kno ckout 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 appropria te 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 P450 s, carboxylesterases, butyrlcholinesterase) are likely to impact potential population sensitivit y, rendering the results of the PON1 data, by themselves, insufficiently reliable to support a re gulatory 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 stat es that the “correlati on between PON-1 genotype, cholinesterase activity, and clin ical toxicity needs to be fu rther evaluated.” Population variability data on PON1 would be more usef ul 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 ep idemiological studies have been published that considered the association between PON1 status/genotype and health outcome. Hofmann et al. (2009) recently reported associations between PON1 stat us and inhibition of butyrylcholinesterase in a group of pesticide handlers in Washington. The aut hors note that this st udy 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 I nhibition in Relation to Paraoxonase-1 (PON1) Status among OrganophosphateExposed Agricultural Pesticide Handlers./ E nviron 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 fr om this study. The Q/R-192 and/or C/T -108 polymorphism at the promoter site have been ev aluated recently as a fact or affecting birth or neurobehavioral outcomes following ge stational 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 Furl ong et al. study supports an intra-species uncertainty factor of over 164X given the range of variability seen in th at study. The 164X value is derived from sensitivity observed in transg enic mice expressing human PON1Q-192 compared with mice expressing human PON1R-192 combined w ith 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-new born pairs from the CHAMAC OS (Center for the Health

Assessment of Mothers and Ch ildren of Salinas) cohort.

EPA believes it is fundamentally at odds with international risk a ssessment 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 si ngle 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 uncertain ty factor derived from the Furlong et al. study would take this practice one step further by re lying upon combined PON1 values from different species with differing overall metabolic activity to derive the intra-specie s factor. EPA does not believe this approach is an a ppropriate means of determining th e 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 th e 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-sp ecies factors should be extrapol ated 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 Or ganophosphates, 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 a pplication of an intra-species factor that accounts for the full range of sensitivity across a species. Since EPA does not de velop its PoDs in this fashion; the approach suggested by petitioners is not appropriate.

In summary, the Agency has carefully cons idered the issue of PON1 variability and determined that data addressing PON1 in isolat ion are not appropriate fo r use alone in deriving an intra-species uncertainty fact or. 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 Fu rlong et al. derivation is inappropriate and inconsistent with international risk assessment practice. 42 Finally, petitioners’ statement that the Furlong et al. study supports an in tra-species uncertainty factor of at least 150X likely overstates potential variability. While EPA does believe that further research in th is area may be required, in part, because multiple factors most likely imp act potential population sensitivity, at this time, there is no scientific basis for departing from the standard 10-fold intra-sp ecies uncertainty factor for extrapolating variability based on PON1. The Agency will continue to monitor the scientific literature regarding PON1. At th is point in time, however, peti tioners’ claims regarding PON1 would not be a factor in any ri sk determination the Agency might make to revoke chlorpyrifos

tolerances. EPA therefore inte nds to deny this aspect of th e petition when it publishes its response to the petition in the Federal Register.

2. Endocrine Disrupting Effects

a. Petitioners’ claim

Petitioners summarize a numberof studies evaluating the e ffects of chlorpyrifos on the endocrine system, asserting that, taken together, the studies “suggest that chlorpyrifos may be an endocrine disrupting chemical, capable of in terfering with multiple hormones controlling reproduction and neurodevelopment.” The petitione rs then assert that EPA should not have delayed consideration of endocrine effects ab sent finalization of th e Endocrine Disruptor Screening Program 43 (EDSP) and should have quantitativel y 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 a nd a request that EPA undertake quantitative incorporation of endocrine endpoints into its assessment of chlor pyrifos. The petition does not explain whether

and how endocrine effects should fo rm the basis of a decision to revoke tolerances. The basis for seeking revocation of a tolerance is a showing that the pesticide is not “s afe.” Petitioners have

neither asserted that EPA should revoke tolera nces 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 pe tition appears to colle ct a number of studies suggesting that chlorpyrifos may have effects on the endocrine system and that EPA should have considered those health impacts at reregistrati on in a quantitative assessment.

To the extent that petitioners are seek ing 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 sens itive than the PoDs cu rrently used in the chlorpyrifos risk assessment. While the cited studies provide qualitative information that exposure to chlorpyrifos may be associated w ith effects on the androge n and thyroid hormonal pathways, these data alone do not demonstrate that current human exposures from existing tolerances are unsafe. The Agency noted sim ilar effects during its ev aluation 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 th e 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 i ndicate 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, inte nds to deny this portion of the petition when it publishes its response to the petiti on 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 f iling 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 rece ive EDSP Tier 1 test orde rs. 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 intende d to allow EPA to determine whether certain substances (including pesticide ac tive 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 esta blish a quantitative, dose-response relationship for any adverse effect s that might result from the interactions with the endocrine

system.

On November 5, 2009, EPA issued Tier 1 test or ders to the registra nts 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 or der recipients agreed to conduct 9 of the 11 assays that comprise the EDSP Tier 1 sc reening 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 a nd 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 Scien tifically Relevant Information (OSRI) that had been submitted, EPA de termined 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 interactio n 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 un answered questions in th e studies cited in the OSRI submissions. The study deficiencies includ ed the lack of thyroi d weights and thyroid hormone measurements. In addition, organ weig hts and histopathology da ta were obtained in adult animals, whereas in the Tier 1 female pube rtal 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 recipi ents 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 al l 11 Tier 1 screening assays and is in the data review process. EPA intends to review these chlorpyr ifos data as part of its larger process for revi ewing 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 performan ce review results will be submitted for external scientific peer review by the FIFRA SAP in fiscal year 2013. Sp ecifically, EPA intends to first review the data from each individual assay for se veral chemicals to ensure that EPA consistently interprets the measurements for particular e ndpoints in that assay; e.g., EPA will review the thyroid weight measurements reported in the male pubertal assays from a nu mber of chemicals to ensure that the Agency reaches consistent c onclusions as to the significance of the reported results. After that process has been comple ted, EPA will evaluate each chemical’s response across the battery of 11 assays to determine whet her there is evidence of interaction with the estrogen, androgen, and/or t hyroid hormone systems.

EPA believes that the results from the entire ba ttery 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/#!documen tDetail;D=EPA-HQ- OPP-2009-0634-0159

.15 substance may have an effect similar to an eff ect produced by a naturally occurring hormone (FR Vol, 63, No. 248/Monday December 28, 1998). In othe r words, a positive result in the Tier 1 screening assays would not be sufficient to make the determin ation of whether chlorpyrifos interacted with the endocrine system. The cita tions included in the pe tition referred to as evidence that chlorpyrifos may affect estroge n, androgen, and thyroid ho rmonal pathways do not establish quantitative, dose-respons e relationships for potential e ndocrine 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 an y potential effects identified through Tier 1 screening, and to establish the dose response re lationships 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 endoc rine disruption through the Agen cy’s standard EDSP process, as explained above, is the appr opriate approach to address petitioners’ request that EPA incorporate endocrine effects into its risk assessment for chlorpyrif os. This is a transparent and scientifically sound process that has been the subject of external peer review 47 and is designed to

ensure that all data are appropriately considered. By relying on this robu st scientific process, EPA believes that it will ultimately reach a final, scientifically credible determination more efficiently than if EPA were to conduct repeat ed reviews of the data in piecemeal and without

context.

3. Cancer Risks

a. Petitioners’ claim

Petitioners claim that the Agency “ig nored” 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 si gnificant association with chlorpyrifos exposure. The petition then asserts that these data are highly relevant and

46 U.S. EPA (2011), Endocrine Disruptor Screening Prog ram: Weight-of-Evidence: Evaluating Results of EDSP Tier 1 Screening to iden tify 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, Sa ndler 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. (hereinaft er Lee et al. 2004).

49 Petition at 1016 therefore should have been referenced in the fi nal 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 ba sis for seeking revocati on 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 chlo rpyrifos poses an unsaf e carcinogenic risk. Petitioners have not presented such an analysis . Accordingly, when EPA publishes its response to the petition in the Federal Register, EPA in tends to deny the petitioners’ request to revoke chlorpyrifos tolerances or cancel chlorpyrifos registrations to th e 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 chlo rpyrifos’ carcinogenic potential, and therefore does not alter the Agency's current cancer clas sification for chlorpyrifos. Specifically, the Agency does not believe this evidence rais es sufficient grounds for concern regarding chlorpyrifos that EPA should consider initiati ng action based upon this information that might lead to revocation of the chlorpyr ifos tolerances or can cellation of the chlorpyrifos registrations.

The Agency was aware of the December 2004 study cited by petitioners. While Lee et al. observed a possible association be tween chlorpyrifos use and the incidence of lung cancer, the

authors also stressed that furt her 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 unmeas ured confounding factors or confounding factors not fully accounted for in the analysis, and possible fa lse 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 worki ng closely with the AHS researchers to clearly

understand the results of their research efforts to ensure the Agency approp riately 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 associ ation with specific anatomical cancer sites, in addition to the previously published cohort study 52 cited by the petitioners. As noted below, both the Agency and Health Canada have comprehensively revi ewed 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 Evaluatio ns 2003-2009. (hereinafter Christenson 2011).

51 Lee et al. 2004 at 1788.

52 Lee et al 2004.17 proposed a draft framework 53 to consider epidemiologic info rmation in the risk assessment process, and additionally utilized AHS data in a case study illustrati ng the similarities and differences in exposure assessment methodology be tween epidemiologic research and regulatory

risk assessment.

In accordance with the Agency’s 2005 Gu ideline 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 chlorpyrif os in their feed every day of their lives (78 weeks for mice and 104 weeks for rats) at doses t housands of times greater than any anticipated exposure to humans from authorized uses. Ther e 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 pot ential 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 potenti al of chlorpyrifos. 55
EPA concluded with respect to the AHS lung cancer results that the find ings are useful for generating hypotheses, but require confirmation in future studies. This conclusion is consistent

with that of researchers from Health Ca nada. Specifically, We ichenthal et al. (2010) 56 recently published a review article in Environmental H ealth Perspectives on pesticide exposure and

cancer incidence in the AHS cohort. Their revi ew of these same studies concluded that the weight of experimental toxicological evidence does not suggest that chlorpyrifos is carcinogenic, and that epidemiologic results currently ava ilable from the AHS are inconsistent, lack replication, and lack a coherent biologically plausible carcinogeni c 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 suggestiv e epidemiological eviden ce of an association between chlorpyrifos and lung cancer to only fo rm a hypothesis as to a carcinogenic mode of action, additional research (includi ng follow-up AHS research) is need ed to test the hypothesis. Consequently, at this time it is reasonable to conclude chlorpyrif os is not a carcinogen in view of the lack of carcinogenicity in the rodent bioassays and the la ck of a genotoxic or mutagenic potential. The Agency concludes that existing ep idemiological data (including Lee et al.) do not change the current weight of the evidence conclusi ons. The Agency continues to believe there is

not a sufficient basis to alter its assessment of ch lorpyrifos as not likely to be carcinogenic to humans when multiple lines of evidence are considered (e.g., epidemiology findings, rodent bioassay, genotoxicity); therefore, ch lorpyrifos cancer risk would not be a factor in any potential Agency risk determination to re voke tolerances for chlorpyrifos.

53 U.S. EPA Presentation to the FIFRA Science Advi sory 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, fail ed to apply FQPA10X Safety Factor

a. Petitioners’ claim

Petitioners assert that EPA re lied 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 safe ty factor for chlor pyrifos in the CRA.

b. Agency Response

Petitioners’ assertions do not provide a sufficient basis for revoking chlorpyrifos tolerances. As explained prev iously, the ground for seeking re vocation of a tolerance is a showing that the pesticide is not “safe.” Th e petitioners’ claim that the data EPA relied upon support a different FQPA safety factor for chlorp yrifos in the CRA does not amount to a showing that chlorpyrifos tolerances are unsafe. To s how a lack of safety, petitioners would have to present a factual analysis demons trating 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 publis hes 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 ba sed on the results of th e Zheng et al. study.

Despite the inadequacy of petitioners’ FQPA sa fety factor claims, EPA has examined the evidence cited by petitioners for the purpose of evaluating whether the evidence raises sufficient grounds for concern regarding chlor pyrifos that EPA should consider initiating action that might

lead to revocation of the chlorpyrifos tolerances.

In general, when the Agency conducts a cumu lative 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 a nd 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 appr oximately 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 stabilit y of the AChE inhibition.

57 Petition at 16.

58 Zheng Q, Olivier K, Won YK, Pope CN. 2000. Compara tive cholinergic neurotoxicity of oral chlorpyrifos exposures in preweaning and adult rats. Toxicological Scien ces, 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 po st-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 da m 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 dete rmining the magnitude of the FQPA safety factors in the OP CRA. Furthermore, because ch aracteristics of children are directly accounted for in the cumulative exposure assessment, th e 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 derive d safety factor. To best match the relative potency factor and PODs based on repeated dosing, the Agency used repeated dosing data in juvenile s 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 th e 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 va lues were reported for chlorpyrifos. In determining the FQPA safety fact or, petitioners claim that the Ag ency 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 m onotonic 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 th e response curve, relevant for human exposures and, thus, the cumulative risk assessment (i.e., at or near the 10% inhibiti on level), little to no difference is observed. Therefore, despite the la ck 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 pa rt of the 2011 preliminary chlorpyrifos HHRA 61
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 ar e specially designed studies to compare the dose-response relationship in juvenile and adu lt rats. This CCA study includes two components: 1) acute, single dosing in post-natal day (PND) 11 and young a dult rats and 2) 11-days of repeating dosing in rat pups from PND11-21 and 11-days of rep eated 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 Heal th Risk Assessment for Registration. Available in docket number EPA-HQ-OPP-2008-0850, http://www.regulations.gov/#!do cumentDetail;D=EPA-HQ-OPP-2008-

0850-0025

.20 repeated dosing portion of the study, the BMD 10s of 0.80 (0.69 BMDL 10 ) and 1.0 (0.95 BMDL 10 ) mg/kg/day respectively for female pups and adults re sults 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 fo r chlorpyrifos. As su ch, 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 revo ke 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 determin e that chlorpyrifos coul d be re-registered and

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

defensible. 63

b. Agency Response

This portion of the petition does not purpor t to be an independent basis for revoking chlorpyrifos tolerances or cance lling 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 fa vor 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 cl aims, EPA’s response to the specific studies are, therefore, addressed in its responses to pe titioners’ 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 signifi cance accorded all data utilized to inform risk management decisions. Regist rant 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 designe d 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 evaluati ng any study, is its scient ific soundness and quality, and thus, the level of confidence in the study fi ndings to contribute to the risk assessment.

The literature was searched, fully consider ed, 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 chlorpyr ifos SAP paper and the chlorpyr ifos 2011 preliminary HHRA.

Therefore, by evaluating registrant da ta in accordance with in ternationally harmonized and scientifically peer -reviewed study protocols, undertaki ng thorough open lite rature 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 respons e to petitioners’ claims regarding the Agency’s inadequate use of various data only further highlig hts and supports the scientifically defensible results of the Agency’s assessment. Petitioners’ cl aim 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 ch lorpyrifos tolerances or cancel chlorpyrifos registrations.

6. Export Hazard

a. Petitioners’ claim

Petitioners assert that EPA must ban chlo rpyrifos and cancel a ll tolerances because, otherwise, chlorpyrifos will continue to be us ed unsafely by workers, including children, in other countries who may not utilize worker protect ion equipment required for use in the U.S. 65 In addition, petitioners assert that continued chlorp yrifos 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 pub lic health and the environment throughout the

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

address risk from domestic use of pesticides and from pesticide re sidues 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 Pestic ides. 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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