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Federal Register / Vol. 86, No. 165 / Monday, August 30, 2021 / Rules and Regulations Epidemiologic & Incident Data in Risk Assessments in Pesticides, described the use of the Bradford Hill Criteria as modified in the Mode of Action Framework to integrate epidemiology information with other lines of evidence. As suggested by the 2010
FIFRA SAP, EPA did not immediately finalize the draft framework but instead used it in several pesticide evaluations prior to making revisions and finalizing it. EPAs Office of Pesticide Programs OPP finalized this epidemiology framework in December 2016 Ref. 5.
In 2011, EPA released its preliminary human health risk assessment 2011
HHRA for the registration review of chlorpyrifos. The 2011 HHRA used 10%
RBC AChE inhibition from laboratory rats as the critical effect or PoD for extrapolating risk. It also used the default 10X uncertainty factors for interand intra-species extrapolation. The 10X
FQPA SF was removed with a note to the public that a weight of evidence WOE evaluation would be forthcoming, as described in the 2010
draft Framework for Incorporating Human Epidemiologic & Incident Data in Health Risk Assessment.
In 2011, EPA convened a meeting of the FIFRA SAP to review the PBPKPD
model for chlorpyrifos. The panel made numerous recommendations for the improvement of the model for use in regulatory risk assessment, including the inclusion of dermal and inhalation routes. From 20112014, Dow AgroSciences, in consultation with EPA, refined the PBPKPD model, and those refinements were sufficient to allow for use of the PBPKPD model in the next HHRA.
In 2012, the Agency convened another meeting of the FIFRA SAP to review the latest experimental data related to RBC
AChE inhibition, cholinergic and noncholinergic adverse outcomes, including neurodevelopmental studies on behavior and cognition effects. The Agency also performed an in-depth analysis of the available chlorpyrifos biomonitoring data and of the available epidemiologic studies from three major childrens health cohort studies in the United States, including those from the CCCEH, Mount Sinai, and University of California, Berkeley. The Agency explored plausible hypotheses on mode of actions/adverse outcome pathways MOAs/AOPs leading to neurodevelopmental outcomes seen in the biomonitoring and epidemiology studies.
The 2012 FIFRA SAP described the Agencys epidemiology review as very clearly written, accurate and very thorough review. Ref. 6 at 5052, 53
It went further to note that it believes
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that the Agencys epidemiology review appropriately concludes that the studies show some consistent associations relating exposure measures to abnormal reflexes in the newborn, pervasive development disorder at 24 or 36
months, mental development at 79
years, and attention and behavior problems at 3 and 5 years of age. . . . . The 2012 FIFRA SAP
concluded that the RBC AChE
inhibition remained the most robust dose-response data, though expressed significant concerns about the degree to which 10% RBC AChE inhibition is protective for neurodevelopmental effects, pointing to evidence from epidemiology, in vivo animal studies, and in vitro mechanistic studies, and urged the EPA to find ways to use the CCCEH data.
In 2014, EPA released a revised human health risk assessment 2014
HHRA. Ref. 7. The revised assessment used the chlorpyrifos PBPKPD model for deriving human PoDs for RBC AChE
inhibition, thus obviating the need for the inter-species extrapolation factor as explained later in this Unit and providing highly refined PoDs which accounted for gender, age, duration and route specific exposure considerations.
The PBPKPD model was also used to develop data derived intra-species factors for some lifestages. The 10X
FQPA SF was retained based on the outcome of the 2012 FIFRA SAP and development of a WOE analysis on potential for neurodevelopmental outcomes according to EPAs Framework for Incorporating Human Epidemiologic & Incident Data in Risk Assessments for Pesticides. The 2014
HHRA, taken together with the Agencys drinking water assessment, identified estimated aggregate risks exceeding the level of concern for chlorpyrifos.
On November 6, 2015, EPA issued a proposed rule to revoke all tolerances of chlorpyrifos, based on the aggregate risks exceeding the level of concern 80
FR 69079 FRL993592. In this proposed rulemaking, EPA specified that it was unable to conclude that aggregate exposures from use of chlorpyrifos met the FFDCAs reasonable certainty of no harm standard due to risks identified from the drinking watering using a national-scale assessment i.e., using default values and conservative assumptions. At that time, the EPA had not completed a refined drinking water assessment i.e., a higher-tier and more resourceintensive assessment relying on more targeted inputs or an additional analysis of the hazard of chlorpyrifos that was suggested by several commenters to the 2014 HHRA. Those
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commenters raised the concern that the use of 10% RBC AChE inhibition for deriving PoDs for chlorpyrifos may not provide a sufficiently health protective human health risk assessment given the potential for neurodevelopmental outcomes.
In 2015, EPA conducted additional hazard analyses using data on chlorpyrifos levels in fetal cord blood reported by the CCCEH study investigators. The Agency convened another meeting of the FIFRA SAP in April 2016 to evaluate a proposal of using cord blood data from the CCCEH
epidemiology studies as the source of data for the PoDs. The 2016 SAP did not support the direct use of the cord blood and working memory data for deriving the regulatory endpoint, due in part to insufficient information about timing and magnitude of chlorpyrifos applications in relation to cord blood concentrations at the time of birth, uncertainties about the prenatal windows of exposure linked to reported effects, lack of a second laboratory to reproduce the analytical blood concentrations, and lack of raw data from the epidemiology study. Ref.
8 Despite its critiques of uncertainties in the CCCEH studies, the 2016 FIFRA
SAP expressed concern that 10% RBC
AChE inhibition is not sufficiently protective of human health.
Specifically, the FIFRA SAP stated that it agrees that both epidemiology and toxicology studies suggest there is evidence for adverse health outcomes associated with chlorpyrifos exposures below levels that result in 10% RBC
AChE inhibition i.e., toxicity at lower doses. Id. at 18. Ref. 8
Taking into consideration the conclusions of the 2016 SAP, EPA
issued another HHRA using a dose reconstruction approach to derive the PoD based on the neurodevelopmental effects observed in the CCCEH study. In 2016, EPA also issued a revised drinking water assessment 2016 DWA.
EPA issued a Notice of Data Availability seeking public comment on the 2016
HHRA and 2016 DWA. 81 FR 81049, November 17, 2016 FRL995465.
In 2017, in response to a Ninth Circuit order, EPA denied the 2007 Petition on the grounds that further evaluation of the science during the remaining time for completion of registration review is warranted to achieve greater certainty as to whether the potential exists for adverse neurodevelopmental effects to occur from current human exposures to chlorpyrifos. 82 FR at 16583. As part of this commitment to further evaluate the science, EPA evaluated the new laboratory animal studies with results
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