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Federal Register / Vol. 86, No. 165 / Monday, August 30, 2021 / Rules and Regulations
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Federal Advisory Committees and external review panels have encouraged the use of such a modeling approach to reduce inherent uncertainty in the risk assessment and facilitate more scientifically sound extrapolations across studies, species, routes, and dose levels. The PBPKPD model for chlorpyrifos has undergone extensive peer review by various individual or groups, including the FIFRA SAPs.
Significant improvements have been made to the model over the years in response to recommendations from the 2008, 2011, and 2012 FIFRA SAPs and comments from both internal and external peer reviewers. Ref. 9 at 20.
As a result, EPA has concluded that the current PBPKPD model is sufficiently robust and is using it for deriving PoDs for chlorpyrifos.
a. Derivation of PoDs As noted above, the PoDs for chlorpyrifos are based on the levels at which 10% RBC AChE inhibition is observed. The PBPKPD model accounts for pharmacokinetic and pharmacodynamic characteristics to derive age-, duration-, and route-specific PoDs. Separate PoDs have been calculated for dietary food, drinking water and residential exposures by varying inputs on types of exposures and populations exposed. Specifically, the following characteristics have been evaluated: Duration 24-hour acute, 21day steady state; route dermal, oral, inhalation; body weights which vary by lifestage; exposure duration hours per day, days per week; and exposure frequency events per day eating, drinking. For each exposure scenario, the appropriate body weight for each age group or sex was modeled as identified from the Exposure Factors Handbook Ref. 21 for residential exposures and from the U.S. Department of Agricultures USDA National Health and Nutrition Examination Survey NHANES/What We Eat in America WWEIA Survey for dietary exposures.
Within the PBPKPD model, the Agency evaluated the following exposure scenarios: Oxon chlorpyrifos metabolite exposures via drinking water acute and steady-state exposures for infants, children, youths, and female adults; chlorpyrifos exposures via food acute and steady-state exposures for infants, children, youths, and female adults; steady-state residential exposures to chlorpyrifos via skin for children, youths, and female adults;
steady-state residential exposures to chlorpyrifos via hand-to-mouth ingestion for children 12 years old;
steady-state residential exposures to chlorpyrifos via inhalation for children
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12 years old and female adults. Ref. 9
at 2225.
Steady-state dietary exposure was estimated daily for 21 days. For drinking water exposure, infants and young childrens infants <1 year old, children between 12 years old, and children between 612 years old were assumed to consume water 6 times per day, with a total consumption volume of 0.69 L/day. For youths and female adults, they were assumed to consume water 4 times per day, with a total consumption volume of 1.71 L/day.
For all residential dermal exposures to chlorpyrifos the dermal PoDs were estimated assuming 50% of the skins surface was exposed. Exposure times for dermal exposure assessment were consistent with those recommended in the 2012 Residential Standard Operating Procedures SOPs Ref. 18. For residential inhalation exposures following public health mosquitocide application, the exposure duration was set to 1 hour per day for 21 days. The incidental oral PoDs for children 1 to <2
years old for other turf activities were estimated assuming that there were six events, 15 minutes apart, per day.
The PBPK-modeled PoDs derived for the various lifestages, routes, and exposure scenarios discussed above, can be found in Table 4.2.2.1.2 of the 2020
HHRA Ref 8.
b. Inter-Species Extrapolation As indicated above, the PBPKPD
model directly predicts human PoDs based on human physiology and biochemistry, and thus there is no need for an inter-species uncertainty factor to extrapolate from animal PoDs.
c. Intra-Species Extrapolation The PBPKPD model can account for variability of critical physiological, pharmacokinetic, and pharmacodynamic parameters in a population to estimate, using the Monte Carlo analysis, the distribution of doses that result in 10% RBC AChE inhibition.
Therefore, Data-Derived Extrapolation Factors DDEF for intra-species extrapolation have been estimated to replace the default intra-species uncertainty factor for some groups Ref.
22.
According to EPAs DDEF guidance Ref. 22, when calculating a DDEF
intra-species extrapolation factor, administered doses leading to the response level of interest in the case of chlorpyrifos, the 10% change in RBC
AChE inhibition are compared between a measure of average response and response at the tail of the distribution representing sensitive individuals. The
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tail of the distribution may be selected at the 95th, 97.5th, and 99th percentile.
As to chlorpyrifos, the 99th percentile was used in risk assessment to provide the most conservative measure Ref. 7.
In addition to estimating DDEF using the above approach for specific age groups, intra-species DDEF was also calculated by comparing between average responses between adults and 6month old infants. For the 2020 HHRA, the largest calculated DDEFs, 4X for chlorpyrifos and 5X for the oxon metabolite, were used for intraspecies extrapolation for all groups except women of childbearing age. There was a slightly higher variability between adults and infants when considering the distributions for the oxon metabolite, thus, the slightly higher intra-species factor. For women of childbearing age, the Agency is applying the standard 10X
intra-species extrapolation factor due to limitations in the PBPKPD model to account for physiological, anatomical, and biochemical changes associated with pregnancy. Ref. 9 at 2122.
d. Summarizing the PoDs, Interand Intra-Species Extrapolation Factors In summary, for assessing the risks from exposure to chlorpyrifos, the human PBPKPD model has been used to derive PoDs based on 10% RBC AChE
inhibition for various populations, durations, and routes. The model, which calculates a human PoD directly, obviates the need for an interspecies extrapolation factor since animal data are not used. To account for variations in sensitivities, the Agency has determined that an intra-species factor of 4X for chlorpyrifos and 5X for the oxon is appropriate for all groups except women of childbearing age. For women of childbearing age, the typical 10X
intra-species factor is being applied, due the lack of appropriate information and algorithms to characterize physiological changes during pregnancy.
3. FQPA Safety Factor As noted above, the FFDCA requires EPA, in making its reasonable certainty of no harm finding, that in the case of threshold effects, an additional tenfold margin of safety for the pesticide chemical residue and other sources of exposure shall be applied for infants and children to take into account potential preand postnatal toxicity and completeness of data with respect to exposure and toxicity to infants and children. 21 U.S.C. 346Ab2C.
Section 408b2C further states that the Administrator may use a different margin of safety for the pesticide chemical residue only if, on the basis of
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