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Federal Register / Vol. 86, No. 165 / Monday, August 30, 2021 / Rules and Regulations
among these only studies from Carr laboratory at Mississippi State University are considered by EPA to be high quality. EPA has concluded that the laboratory animal studies on neurodevelopmental outcomes are not sufficient for quantitatively establishing a PoD. Moreover, EPA has further concluded that the laboratory animal studies do not support a conclusion that adverse neurodevelopmental outcomes are more sensitive than 10% RBC AChE
inhibition. Ref. 8 at 2531, Ref. 9 at 88
89.
EPA evaluated numerous epidemiological studies on chlorpyrifos and other OP pesticides in accordance with the Framework for Incorporating Human Epidemiologic & Incident Data in Health Risk Assessment. Ref. 8, 14, and 15 The most robust epidemiologic research comes from three prospective birth cohort studies. These include: 1
The Mothers and Newborn Study of North Manhattan and South Bronx performed by the Columbia Childrens Center for Environmental Health CCCEH at Columbia University; 2 the Mount Sinai Inner-City Toxicants, Child Growth and Development Study or the Mt. Sinai Child Growth and Development Study; and 3 the Center for Health Assessment of Mothers and Children of Salinas Valley CHAMACOS conducted by researchers at University of California Berkeley.
Ref. 8 at 3243.
In the case of the CCCEH study, which specifically evaluated the possible connections between chlorpyrifos levels in cord blood and neurodevelopmental outcomes on a specific cohort, there are a number of notable associations. Ref. 8 at 3638.
Regarding infant and toddler neurodevelopment, the CCCEH authors reported statistically significant deficits of 6.5 points on the Psychomotor Development Index at three years of age when comparing high to low exposure groups. Notably, these decrements persist even after adjustment for group and individual level socioeconomic variables. These investigators also observed increased odds of mental delay and psychomotor delay at age three when comparing high to low exposure groups. The CCCEH authors also report strong, consistent evidence of a positive association for attention disorders, attention deficit hyperactivity disorder ADHD, and pervasive development disorder PDD when comparing high to low chlorpyrifos exposure groups.
Moreover, it was reported that for children in the CCCEH cohort at age seven for each standard deviation increase in chlorpyrifos cord blood exposure, there is a 1.4% reduction in
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Full-Scale IQ and a 2.8% reduction in Working Memory. In addition, the CCCEH authors evaluated the relationship between prenatal chlorpyrifos exposure and motor development/movement and reported elevated risks of arm tremor in children around 11 years of age in the CCCEH
cohort.
Notwithstanding the observed associations, EPA and the 2012 and 2016 FIFRA SAPs identified multiple uncertainties in the CCCEH
epidemiology studies Ref. 6 and 8.
Some of these include the relatively modest sample sizes, which limited the statistical power; exposure at one point in prenatal time with no additional information regarding postnatal exposures; representativeness of a single point exposure where time-varying exposures or the ability to define cumulative exposures would be preferable; lack of specificity of a critical window of effect and the potential for misclassification of individual exposure measures; and lack of availability of the raw data from the studies that would allow verification of study conclusions.
One of the notable uncertainties in the CCCEH epidemiology studies identified by EPA and the 2016 FIFRA SAP is the lack of specific exposure information on the timing, frequency, and magnitude of chlorpyrifos applications in the apartments of the women in the study.
Despite extensive effort by EPA to obtain or infer this exposure information from various sources, the lack of specific exposure data remains a critical uncertainty. EPA made efforts in 2014 and 2016 to develop dose reconstruction of the exposures to these women. These dose reconstruction activities represent the best available information and tools but are highly uncertain. In addition, the pregnant women and children in the CCCEH
studies were exposed to multiple chemicals, including multiple potent AChE inhibiting OPs and N-methyl carbamates. Moreover, using EPAs dose reconstruction methods from 2014
suggest that the pregnant women likely did not exhibit RBC AChE inhibition above 10%. The 2012 and 2016 FIFRA
SAP reports expressed concern that it is likely that the CCCEH findings occurred at exposure levels below those that result in 10% RBC AChE inhibition Ref. 6 and 8. However, given the available CCCEH exposure information and the exposures to multiple potent AChE inhibiting pesticides, EPA cannot definitively conclude the level of AChE
inhibition. EPA remains unable to make a causal linkage between chlorpyrifos exposure and the outcomes reported by
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CCCEH investigators. Ref. 8 Moreover, given the uncertainties, particularly in the exposure information available from CCCEH single timepoints, lack of time varying exposure, lack of knowledge about application timing, uncertainties remain about the dose-response relationships from the epidemiology studies.
Finally, there are several lines of evidence for actions of chlorpyrifos distinct from the classical mode of action of AChE inhibition. This information has been generated from model systems representing different levels of biological organization and provide support for molecular initiating events binding to the morphogenic site of AChE, muscarinic receptors, or tubulin, cellular responses alterations in neuronal proliferation, differentiation, neurite growth, or intracellular signaling, and responses at the level of the intact nervous system serotonergic tone, axonal transport.
Among the many in vitro studies on endpoints relevant to the developing brain available for chlorpyrifos, only three have identified outcomes in picomole concentrations, including concentrations lower than those that elicit AChE inhibition in vitro.
However, as is the case for many other developmental neurotoxicants, most of these studies have not been designed with the specific goal of construction or testing an adverse outcome pathway.
Thus, there are not sufficient data available to test rigorously the causal relationship between effects of chlorpyrifos at the different levels of biological organization in the nervous system. Ref. 8 at 2731
Due to the complexity of nervous system development involving the interplay of many different cell types and developmental timelines, it is generally accepted that no single in vitro screening assay can recapitulate all the critical processes of neurodevelopment.
As a result, there has been an international effort to develop a battery of new approach methodologies NAMs to inform the DNT potential for individual chemicals. This DNT NAM
battery is comprised of in vitro assays that assess critical processes of neurodevelopment, including neural network formation and function, cell proliferation, apoptosis, neurite outgrowth, synaptogenesis, migration, and differentiation. In combination the assays in this battery provide a mechanistic understanding of the underlying biological processes that may be vulnerable to chemicallyinduced disruption. It is noteworthy, however, that to date the quantitative relationship between alterations in these
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