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Federal Register / Vol. 86, No. 165 / Monday, August 30, 2021 / Rules and Regulations
suggesting effects on the developing brain occur at doses lower than doses that cause AChE inhibition, and concluded that they are not sufficient for setting a PoD. While EPA sought to verify the conclusions of the epidemiology studies conducted by Columbia University it has been unable to confirm the findings of the CCCEH
papers or conduct alternative statistical analyses to evaluate the findings. In summary, while EPA sought to address the potential neurodevelopmental effects associated with chlorpyrifos exposure over the past decade, these efforts ultimately concluded with the lack of a suitable regulatory endpoint based on these potential effects.
However, these efforts do not alleviate the Agencys concerns regarding potential neurodevelopmental effects.
In October 2020, EPA released its latest human health risk assessment 2020 HHRA and drinking water assessment 2020 DWA. Ref. 9 and 10
Due to the shortcomings of the data upon which the 2016 HHRA was based and the uncertainty surrounding the levels around which neurodevelopmental effects may occur, the 2020 HHRA uses the same endpoint and PoDs as those used in the 2014
HHRA i.e., the PBPKPD model has been used to estimate exposure levels resulting in 10% RBC AChE inhibition following acute single day, 24 hours and steady state 21-day exposures for a variety of exposure scenarios for chlorpyrifos and/or chlorpyrifos oxon.
The 2020 HHRA retained the default 10X FQPA SF, but also presented risk estimates at a reduced 1X FQPA SF, though it did not adopt or attempt to justify use of this approach.
Then, in December 2020, as part of its FIFRA registration review, EPA issued its Proposed Interim Registration Review Decision 2020 PID for chlorpyrifos 85 FR 78849, December 7, 2020 FRL1001713. The 2020 PID
was based on comparing estimates in the 2020 HHRA with the values from the 2020 DWA, and retaining the 10X
FQPA safety factor, the PID proposed to limit applications of chlorpyrifos in this country would be reduced to certain uses in certain regions of the United States. The PID proposed to conclude that the Agency could make a safety finding for the approach in this path forward, as risk would be based on limited uses in limited geographic areas, as specified. This proposed path forward was intended to offer to stakeholders a way to mitigate the aggregate risk from chlorpyrifos, which the Agency had determined would exceed risk levels of concern without the proposed use restrictions.

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In December 2020, EPA requested public comment on the 2020 PID, 2020
HHRA, and 2020 DWA. EPA extended the 60-day comment period by 30 days and it closed on March 7, 2021.
VI. EPAs Hazard Assessment for Chlorpyrifos A. General Approach to Hazard Identification, Dose-Response Assessment, and Extrapolation Any risk assessment begins with an evaluation of a chemicals inherent properties, and whether those properties have the potential to cause adverse effects i.e., a hazard identification. In evaluating toxicity or hazard, EPA
reviews toxicity data, typically from studies with laboratory animals, to identify any adverse effects on the test subjects. Where available and appropriate, EPA will also take into account studies involving humans, including human epidemiological studies. The animal toxicity database for a conventional, food use pesticide usually consists of studies investigating a broad range of endpoints including potential for carcinogenicity, mutagenicity, developmental and reproductive toxicity, and neurotoxicity.
These studies include gross and microscopic effects on organs and tissues, functional effects on bodily organs and systems, effects on blood parameters such as red blood cell count, hemoglobin concentration, hematocrit, and a measure of clotting potential, effects on the concentrations of normal blood chemicals including glucose, total cholesterol, urea nitrogen, creatinine, total protein, total bilirubin, albumin, hormones, and enzymes such as alkaline phosphatase, alanine aminotransferase and cholinesterases, and behavioral or other gross effects identified through clinical observation and measurement. EPA examines whether adverse effects are caused by different durations of exposure ranging from short-term acute to long-term chronic pesticide exposure and different routes of exposure oral, dermal, inhalation. Further, EPA
evaluates potential adverse effects in different age groups adults as well as fetuses and juveniles. Ref. 11 at 810.
Once a pesticides potential hazards are identified, EPA determines a toxicological level of concern for evaluating the risk posed by human exposure to the pesticide. In this step of the risk assessment process, EPA
essentially evaluates the levels of exposure to the pesticide at which effects might occur. An important aspect of this determination is assessing the relationship between exposure dose
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and response often referred to as the dose-response analysis. In evaluating a chemicals dietary risks, EPA uses a reference dose RfD approach, which typically involves a number of considerations including:
A point of departure PoD:
Typically, the PoD is the value from a dose-response curve that is at the low end of the observable data in laboratory animals and that is the toxic dose that serves as the starting point in extrapolating a risk to the human population, although a PoD can also be derived from human data as well. PoDs are selected to be protective of the most sensitive adverse toxic effect for each exposure scenario, and are chosen from toxicity studies that show clearly defined No Observed Adverse Effect Levels NOAELs or Lowest Observed Adverse Effect Levels LOAELs, doseresponse relationships, and relationships between the chemical exposure and effect. EPA will select separate PoDs, as needed, for each expected exposure duration e.g., acute, chronic, short-term, intermediate-term and route of exposure e.g., oral, dermal, inhalation. For chlorpyrifos, as discussed later in this Unit, EPA
derived PoDs based on 10% RBC AChE
inhibition.
Interspecies extrapolation: Because most PoDs are derived from toxicology studies in laboratory animals, there is a need to extrapolate from animals to humans. In typical risk assessments, a default tenfold 10X uncertainty factor is used to address the potential for a difference in toxic response between humans and animals used in toxicity tests. For chlorpyrifos, as described further below, EPA used a sophisticated model called a physiologically based pharmacokinetic-pharmacodynamic PBPKPD model that accounts for differences in laboratory animals and humans, thereby obviating the need for the default interspecies factor.
Intraspecies extrapolation: To address the potential for differences in sensitivity in the toxic response across the human population, EPA conducts intraspecies extrapolation. In typical risk assessments, a 10X default uncertainty factor is used. For chlorpyrifos, the PBPKPD model used to derive PoDs also accounts for differences in metabolism and toxicity response across the human population for some age groups and some subpopulations, which allows the default factor of 10X to be refined in accordance with EPAs 2014 Guidance for Applying Quantitative Data to Develop Data-Derived Extrapolation Factors for Interspecies and Intraspecies Extrapolation.

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