Di phthalate metabolites may alter thyroid hormone levels in men

Environmental Health Perspectives, July, 2007 by John D. Meeker, Antonia M. Calafat, Russ Hauser

BACKGROUND: Phthalates are used extensively in many personal-care and consumer products, resulting in widespread nonoccupational human exposure through multiple routes and media. A limited number of animal studies suggest that exposure to phthalates may be associated with altered thyroid function, but human data are lacking.

METHODS: Concurrent samples of urine and blood were collected from 408 men. We measured urinary concentrations of mono(2-ethylhexyl) phthalate (MEHP), the hydrolytic metabolite of di(2-ethylhexyl) phthalate (DEHP), and other phthalate monoester metabolites, along with serum levels of free thyroxine ([T.sub.4]), total triiodothyronine ([T.sub.3]), and thyroid-stimulating hormone (TSH). Oxidative metabolites of DEHP were measured in urine from only 208 of the men.

RESULTS: We found an inverse association between MEHP urinary concentrations and free [T.sub.4] and [T.sub.3] serum levels, although the relationships did not appear to be linear when MEHP concentrations were categorized by quintiles. There was evidence of a plateau at the fourth quintile, which was associated with a 0.11 ng/dL decrease in free [T.sub.4] [95% confidence interval (CI), -0.18 to -0.03] and a 0.05 ng/mL decrease in [T.sub.3] (95% CI, -0.10 to 0.01) compared with the first (lowest) MEHP quintile. The inverse relationship between MEHP and free [T.sub.4] remained when we adjusted for oxidative metabolite concentrations; this simultaneously demonstrated a suggestive positive association with free [T.sub.4].

CONCLUSIONS: Urinary MEHP concentrations may be associated with altered free [T.sub.4] and/or total [T.sub.3] levels in adult men, but additional study is needed to confirm the observed findings. Future studies must also consider oxidative DEHP metabolites relative to MEHP as a potential marker of metabolic susceptibility to DEHP exposure.

KEY WORDS: biomarkers, endocrine disruption, epidemiology, hormone, phthalates, thyroid, urinary metabolites. Environ Health Perspect 115:1029-1034 (2007). doi:10.1289/ehp.9852 available via http://dx.doi.org/[Online 12 March 2007]

Human exposure to some industrial compounds may result in adverse health outcomes mediated through the neuroendocrine axis. These chemicals may affect the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the human body that are responsible for maintaining homeostasis, reproduction, development, and/or behavior [U.S. Environmental Protection Agency (EPA) 1997]. In addition to being essential for normal brain development, thyroid hormones play an important role in many physiologic systems, and alterations in thyroid hormone levels can lead to a myriad of adverse clinical conditions (Nussey and Whitehead 2001). Although much is still unknown about mechanisms and consequences involved with the relationship between environmental exposures and changes in thyroid hormone levels, phthalates and other environmental chemicals may bind to thyroid receptors and influence thyroid hormone signaling (Zoeller 2005).

Phthalates are used extensively in many personal-care and consumer products, resulting in widespread nonoccupational human exposure through multiple routes and media (Hauser and Calafat 2005). High-molecularweight phthalates [e.g., di(2-ethylhexyl) phthalate (DEHP)], are primarily used as plasticizers in the manufacture of flexible vinyl, which is then used in consumer products, flooring and wall coverings, food contact applications, and medical devices [Agency for Toxic Substances and Disease Registry (ATSDR) 2002; Hauser and Calafat 2005]. Low-molecular-weight phthalates [e.g., diethyl phthalate (DEP), dibutyl phthalate (DBP)] are used in personal-care products (e.g., perfumes, lotions, cosmetics), as solvents and plasticizers for cellulose acetate, and in formulating lacquers, varnishes, and coatings, including those used to provide timed releases in some pharmaceuticals (ATSDR 2001; Hauser and Calafat 2005). The Centers for Disease Control and Prevention's (CDC) Third National Report on Human Exposure to Environmental Chemicals (CDC 2005) showed that the majority of males in the United States have detectable concentrations of several phthalate monoesters in urine [monoethyl phthalate (MEP), mono(2-ethylhexyl) phthalate (MEHP), monobutyl phthalate (MBP), and monobenzyl phthalate (MBzP)], reflecting widespread exposure to the parent diester compounds among the general population. Two oxidative metabolites of DEHP, mono-(2-ethyl-5-hydroxylhexyl) phthalate (MEHHP) and mono-(2-ethyl-5oxohexyl) phthalate (MEOHP), were present in most subjects at urinary concentrations higher than those of MEHP, the hydrolytic metabolite of DEHP (CDC 2005).

Animal studies have shown that some phthalates, namely DBP, butylbenzyl phthalate (BBzP), and DEHP, cause testicular toxicity and other adverse male reproductive health outcomes (ATSDR 2001, 2002; Hauser and Calafat 2005), whereas human studies on phthalate exposure and male reproductive health have been inconsistent (Duty et al. 2003a, 2003b; Hauser et al. 2006; Hauser and Calafat 2005; Jonsson et al. 2005; Murature et al. 1987; Rozatti et al. 2002). Studies investigating the association between exposure to phthalates and thyroid function are limited. In animal studies, rats with diets contaminated with DEHP were found to have thyroid alterations and lower plasma thyroxine ([T.sub.4]) concentrations compared with controls (Hinton et al. 1986; Howarth et al. 2001; Poon et al. 1997; Price et al. 1988). In addition, a recent in vitro study reported that DEHP and other phthalates caused changes in the iodide uptake of thyroid follicular cells (Wenzel et al. 2005). A dose-dependent inverse association between DBP and both triiodothyronine ([T.sub.3]) and [T.sub.4] has also been reported in male rats (O'Connor et al. 2002). We are unaware of human studies on phthalates and thyroid function; therefore, we designed the present study to investigate potential relations between biological markers of phthalate exposure and levels of [T.sub.4], [T.sub.3], and thyroid-stimulating hormone (thyrotrophin, TSH) in adult men.