The results of this study suggest that there is a positive relationship between urinary TCPY and serum total T4, and a negative relationship between TCPY and serum TSH, in adolescent males and/or men of reproductive age. There was also evidence of decreased and increased TSH in relation to urinary TCPY among males and females >60 years of age, respectively. These findings add to the existing evidence that exposure to certain organophosphate insecticides or their metabolites may disrupt the hypothalamic-pituitary-thyroid (HPT) axis. However, the exact mechanism of action is not understood, as there are only limited reports to date regarding the relationship between exposure to chlorpyrifos or chlorpyrifos-methyl and thyroid function.
In a human observational study, an inverse association between urinary TCPY and free T4 was reported in 322 adult men of reproductive age recruited through an infertility clinic (Meeker et al., 2006
). This was not consistent with results from the present study, where we observed a positive association between urinary TCPY and total T4 in adolescent males (<18 years) and males 18–40 years of age. However, serum levels of free T4 were not available in NHANES 1999–2002
, and the study of men from an infertility clinic did not measure total T4. In an occupational study of 136 male floriculture workers that examined the association between thyroid hormones (T3, T4, and TSH) and OP exposure, urinary dialkyl phosphate (DAP) concentrations were associated with increased levels of TSH and total T4 which supports the results of this study; however, urinary DAPs may reflect exposure to numerous OPs and exposure to chlorpyrifos more specifically was not assessed in the study (Lacasana et al., 2010
Several animal studies investigating thyroid effects related to chlorpyrifos or other OPs may support our results suggesting that TCPY alters thyroid signaling, though the specific findings have not fully consistent between studies. Our observation of sex differences in these relationships is supported by a couple of these studies, whereas experimental support or explanation for the differences we found related to age is lacking. In a study involving male Wistar albino rats subjected to acute organophosphate (methamidophos; dimethyl phosphoramidothioate) exposure, a decrease in serum T4, T3, and TSH levels was observed and resulted in secondary hypothyroidism and sick euthyroidism (Satar et al 2005
). A decrease in serum T4 levels was also observed in CD1 mice (both in dams and F1) after developmental exposure to chlorpyrifos at doses low enough to not elicit inhibition of brain acetylcholinesterase (AchE) (De Angelis et al., 2009
). Both sexes of F1 CD1 mice showed reduced serum T4 levels, and, perhaps consistent with the present study, a more significant effect was observed in males compared to females (De Angelis et al., 2009
). Jeong et al. (2006)
reported that chlorpyrifos-methyl induces hypothyroidism (decreased serumT4 and increased serum TSH) and altered thyroid and pituitary gland weights through sexual maturation and adulthood in rats after long-term in utero
and postnatal exposure (Jeong et al., 2006
). Interestingly, dose-response relationships between exposure and thyroid hormones appeared stronger among the male rates. Finally, the thyroid disrupting potential of chlorpyrifos was also demonstrated in vitro
by a study of rat pituitary GH3 cells, where chlorpyrifos exposure altered T3-induced cell growth (Ghisari and Bonefeld-Jorgensen, 2005
Our analysis had several limitations. The analysis was based on a single measure of urinary TCPY and serum thyroid hormone levels. Despite the short half-life of chlorpyrifos (approximately 27 hours in the body) and substantial temporal variability in exposure levels over time (CDC, 2010; Meeker et al. 2005
), urinary TCPY is still considered to be the best and most specific biomarker of chlorpyrifos and chlorpyrifos-methyl exposure (Barr et al., 2006). Thyroid hormone levels, especially TSH, may also have significant intraindividual variability over time (Hollowell et al., 2002
; Surks et al., 2005
). Another limitation is that pregnant women, infants, and young children were not included in this analysis. Human and experimental studies have shown that fetuses and infants were more sensitive than adults to many environmental toxicants, including chlorpyrifos (Timchalk et al., 2007
). Also, there is growing evidence of the adverse impact of exposure to chlorpyrifos on fetal growth and early childhood neurodevelopment (Perera et al., 2005
; Eskenazi et al., 2007
; Rauh et al., 2006
; Engel et al., 2011
). Nevertheless, our findings of a relationship between urinary TCPY and markers of thyroid function may help inform potential mechanisms involved in adverse childhood neurodevelopment associated with OP exposure but should be explored in developmental cohort studies.
Despite the above limitations, this is the largest study to date examining the relationship between thyroid hormones and a biomarker of chlorpyrifos exposure in a human population. This will add to the body of knowledge assessing how environmental exposures impact thyroid signaling, which is vital to numerous human physiologic functions.