Inhibition, Na+/I- symporter (NIS) leads to Thyroidal Iodide, Decreased

The thyroid system is quite complex and therefore some inconsistent results have been produced by recent studies. For example, it has been observed in healthy volunteers that a 6-month exposure to perchlorate at doses up to 3 mg/d (low doses) had no effect on thyroid function, including inhibition of thyroid iodide uptake as well as serum levels of thyroid hormones, TSH, and Tg (Braverman et al., 2006). However, this study was limited by the small sample size and is obviously underpowered.

The review by Charnley (2008) examines a number of studies where association between perchlorate environmental (low) exposure and thyroid effects were analysed and many inconsistent conclusions have been drawn. For instance, no correlations were found between TH serum levels and urinary iodine concentrations among women exposed to perchlorate participating in the 2000-2001 National Health and Nutrition Examination Survey (NHANES). Available evidence does not support a causal relationship between changes in TH levels and current environmental levels of perchlorate exposure, but does support the conclusion that the US Environmental Protection Agency's reference dose (RfD) for perchlorate is conservatively health-protective. However, potential perchlorate risks are unlikely to be distinguishable from the ubiquitous background of naturally occurring substances present at much higher exposures that can affect the thyroid via the same biological mode of action as perchlorate, such as nitrate and thiocyanate. Therefore, risk management approaches that account for both aggregate and cumulative exposures and that consider the larger public health context in which exposures are occurring are desirable.

Additionally, a more comprehensive study by Pearce et al. (2010) conducted during 2002-2006 on 22,000 women at less than 16-week gestation showed that while low-level perchlorate exposure was ubiquitous in these women (with a median urinary perchlorate concentration of 5 µg/liter in the Turin cohort and 2 µg/liter in the Cardiff cohort), no associations between urine perchlorate concentrations and serum TSH or free T4 in the individual euthyroid or hypothyroid/hypothyroxinemic cohorts were found.

The data assessing the effect of maternal perchlorate exposure in neonates and children and thyroid function remain unclear (Leung et al., 2010).

Decreased iodine intake can decrease TH production, and therefore exposure to perchlorate might be particularly detrimental in iodine-deficient individuals (Leung et al. 2010). Moreover, biologically based dose-response modeling of the relationships among iodide status (e.g., dietary iodine levels), perchlorate dose, and TH production in pregnant women has shown that iodide intake has a profound effect on the likelihood that exposure to goitrogens will produce hypothyroxinemia (Lewandowski et al. 2015).

Consequences of TH deficiency depend on the developmental timing of the deficiency (Zoeller and Rovet, 2004). For instance, if the TH deficiency occurs during early pregnancy, offspring show problems in visual attention, visual processing and gross motor skills, while if it occurs later, offspring may show subnormal visual and visuospatial skills, slower response speeds and motor deficits. If TH insufficiency occurs after birth, language and memory skills are most predominantly affected (Zoeller and Rovet, 2004). Altogether these studies indicate that factors, such as age, gender, developmental stage, and iodide status can affect the impact of perchlorate and other NIS inhibitors. All these variables should be taken into account to explain possible inconsistencies in study findings.