Our investigation, a secondary analysis of relevant data from the PIN Studies, possesses innovative aspects.
First, available epidemiologic evidence of developmental effects of prenatal OPE exposure is limited, and our investigation will strengthen this body of evidence. More
specifically, our investigation will be the second epidemiologic study of developmental effects of OPE exposures during the sensitive prenatal period, and the third epidemiologic study relating OPE exposure to developmental qualities overall. These two studies, performed by Lipscomb et al. and Castorina et al., have been described above. Briefly, the first investigation of behavioral effects of early life exposure to OPEs was performed by Lipscomb et al. [83], who evaluated cross-sectional associations between ∑OPE concentrations measured in passive silicone samplers worn by children and scores on the Social Skills Improvement Rating Scale in a population of children (n=72) ages three to five years; the investigators reported that greater ∑OPE concentrations in the passive samplers were associated with poorer scores on the Responsibility subscale and greater scores on the Externalizing subscale, both reflecting adverse effects. While suggestive of potential behavioral effects, these findings are somewhat limited by the study’s modest sample size, cross-sectional study design, assessment of only a single exposure pathway (dust and suspended particles), and assessment of exposure during a period of potentially limited sensitivity (i.e., post-natal).
To our knowledge, the only prior epidemiologic study of developmental effects of
prenatal OPE exposure was performed by Castorina et al. [118], who used data from the Center for the Health Assessments of Mothers and Children of Salinas (CHAMACOS) to investigate associations between concentrations of three OPE metabolites (DPHP, BDCIPP, ip-PPP)
measured in urine collected from mothers during pregnancy and offspring’s performance on three psychometric assessments administered at 7 years of age (n’s from 248 to 282). The authors reported that higher concentrations of OPE metabolites (particularly DPHP) in urine during pregnancy were associated with poorer scores on the WISC-IV (particularly the Working Memory scale), and higher scores on the BASC-2 Hyperactivity scale. In an improvement over Lipscomb et al., this study was strengthened by its prospective birth cohort design that allowed for assessment of exposure during the sensitive prenatal period and establishment of
temporality of effects. This study also benefited from administration of a relatively diverse array of developmental instruments, which allowed for assessment of a broad array of developmental endpoints. However, mothers in this study were enrolled between 1999 and 2000, prior to the PBDE phase-out and subsequent increase in OPE usage, therefore exposure levels may not reflect exposures post-PBDE phase-out, which are likely to be higher. Data from the PIN Study indicate that mothers in this population were more highly exposed and experienced a wider distribution of exposures, which will likely support our ability to observe effects of exposure. While these two studies (Lipscomb et al. and Castorina et al.) are generally suggestive of developmental effects of early life OPE exposures, it is necessary to reproduce their findings in other populations to strengthen epidemiologic inference. Ultimately, limitations of observational epidemiology require reproduction of study results and an accumulation of evidence, and our study using data collected by the PIN Studies will contribute to this body of evidence.
Second, our investigation will be the first to estimate developmental effects of exposure to TCIPP. While Lipscomb et al. included TCIPP in their exposure assessment, their final estimates used a summary measure of OPEs (i.e., ∑OPE) and did not specifically investigate associations with TCIPP. Additionally, Castorina et al. [21, 118] measured bis(1-chloro-2-propyl) phosphate (BCIPP), a metabolite of TCIPP, in their analyses, though the detection frequency for this compound was 0% and they were consequently unable to investigate associations with
measured with high frequency in our study sample (98% > MDL). Therefore, our analysis, which will include investigation of associations with BCIPHIPP, and will be the first assessment of developmental effects of TCIPP exposure in humans. This is significant, as previous studies have established that TCIPP exposure is highly prevalent [4, 7, 15, 21, 22, 27, 30, 51, 52, 125, 177-183], and experimental studies have reported associations between TCIPP exposure and endocrine-related [80, 84, 104, 156] and behavioral [114] endpoints, which supports
investigation of this compound’s potential developmental effects.
Third, our investigation will assess cognitive and behavioral dimensions that have not been previously assessed in relation to early life OPE exposure. Assessment of a broad array of developmental endpoints is valuable because, in light of limited observational evidence, it remains unclear which physiologic structures and corresponding developmental qualities are most sensitive to effects of OPE exposures in humans. Therefore, identifying sensitive
endpoints will improve our understanding of developmental effects of OPE exposures and help to guide future research. For example, our investigation will be the first to assess associations between OPE exposure and dysregulation-related qualities (i.e., problems with sleeping, problems with eating, negative emotionality, sensory sensitivity), as assessed by the Infant- Toddler Social Emotional Assessment (ITSEA). The investigation of associations between OPE exposures and the dysregulation-related qualities will be a valuable contribution to our
understanding of developmental effects of OPE exposures in humans, as it will help to either rule out these endpoints as insensitive, or identify them as sensitive endpoints for future study, such that observational researchers can seek to replicate these findings, and experimental researchers can better focus on physiologic qualities (e.g., structures, processes) related to dysregulation. In a similar fashion, our investigation will also be the first to assess associations between OPE exposure and fine motor skills and visual reception, as well as other domains, including aggression, anxiety, atypicality, depression, somatization, withdrawal, and adaptability,
which have not been previously assessed. The identification of either positive or null associations with these qualities will be valuable for the reasons stated above.
Additionally, our investigation will assess associations between early life OPE exposure and domains that are related, but not identical, to those that have been previously assessed. For example, we will assess associations between OPE exposure and vocabulary production and grammatical complexity – qualities measured by the MacArthur-Bates Communicate Development Inventory (MB-CDI). Although other studies have included assessments of linguistic qualities, such as the Communication subscale of the Social Skills Improvement
System Rating Scale (Lipscomb et al.) and the Verbal Comprehension subscale of the Wechsler Intelligence Scale for Children (Castorina et al.), the linguistic qualities measured by the MB-CDI are not identical to those obtained from previous assessments; for example, the measurements obtained from the MB-CDI may reflect more functional endpoints, and neither of the previous assessments have been obtained through parent-report (as opposed to teacher-report or self- report), which provides unique strengths and weaknesses. This is not to suggest that our
assessments will be “superior”, but that these specific related qualities have not been previously assessed. Ultimately, the assessment of novel developmental dimensions and the assessment of related, but not identical, developmental dimensions will provide a more complete picture of developmental effects of early life OPE exposure. Moreover, as noted above, replication of previous findings is also necessary to strengthen available evidence of adverse developmental effects.
CHAPTER 4: APPROACH