Oral (Drinking Water) Developmental Toxicity Study of Ammonium Perchlorate in Sprague-Dawley Rats

Abstract

A developmental toxicity study was conducted with ammonium perchlorate (AP) in the drinking water at doses of 0.0, 0.01, 0.1, 1.0, and 30.0 mg/kg-day beginning 14 days before cohabitation and continuing through sacrifice. Twenty-four rats/group were cesarean-sectioned on day of gestation (DG) 21 and fetuses examined for visceral and skeletal alterations. An additional 16 litters/group were sacrificed on DG 21 for maternal and fetal serum TSH, T(3), and T(4) (thyroid-stimulating hormone, triiodothyronine, and thyroxine) levels and thyroid histopathology. Clinical and necropsy observations, body weights, feed and water consumption, and cesarean-sectioning parameters were comparable among the groups with only delays in ossification observed in the 30 mg/kg-day group. Maternal thyroid weights were increased in the 30.0 mg/kg-day group. Decreased colloid was present in male and female fetal thyroids in the 1.0 and 30.0 mg/kg-day groups. Maternal TSH was increased and T(4) was decreased at all levels, and T(3) was reduced at 30.0 mg/kg-day. Fetal TSH was increased at 1.0 and 30.0 mg/kg-day, T(4) was reduced at 30.0 mg/kg-day, and T(3) was decreased at all levels. The maternal no-observable-adverse-effect level (NOAEL) was 1.0 mg/kg-day; exposures of 30.0 mg/kg-day increased absolute and relative maternal thyroid weights and histopathology findings. The developmental NOAEL was 1.0 mg/kg-day; developmental delays in ossification occurred in the 30.0 mg/kg-day group. The colloid depletion in the thyroids and increased TSH and decreased T(3) and T(4) levels at lower exposures were considered adaptive and not adverse. No adverse effects on development at occurred levels that did not cause maternal toxicity. AP is not a selective developmental toxicant.

A method for the analysis of six thyroid hormones in thyroid gland by liquid chromatography–tandem mass spectrometry

“…These results support the hypothesis that perchlorate can competitively inhibit iodide uptake by the TG via NIS, and can subsequently reduce the production of THs. Although it has been reported that oral administration of perchlorate to rats via drinking water decreased serum T 4 and T 3 , not only in dams but also in fetuses and neonates [27][28][29]35], the results of our study suggest that, instead, the secretion of active THs into the bloodstream is reduced due to reduced TH production in the TG. Furthermore, our results suggest that adverse effects of perchlorate on TH homeostasis are more pronounced under iodide-deficient conditions.…”

Developmental toxicity of thyroid-active compounds in a zebrafish embryotoxicity test

“…In another study with volunteers given perchlorate in drinking water the administered dose was negatively correlated with thyroidal iodide uptake but even a 70% decrease in iodide transport did not result in altered t4 levels (Greer et al, 2002;Strawson et al, 2004). the relatively low developmental toxicity of perchlorate is supported by animal studies showing that pregnant rats and rabbits exposed to a perchlorate dose as high as 30 mg/kg bw/ day do not give birth to offspring with signs of developmental toxicity and changes in thyroid hormone levels were seen as adaptive and reversible (York et al, 2003(York et al, , 2005.…”

Chronic perchlorate exposure impairs stickleback reproductive behaviour and swimming performance

“…Perchlorate is an endocrine disrupting toxicant known to interfere with thyroid hormone production by competitively inhibiting the ability of sodium-iodide symporters to transport iodide into thyroid follicles, which in turn reduces thyroid hormone synthesis (NRC, 2005). Many studies describe histological effects of perchlorate exposure, such as hypertrophied thyroid follicular cells (York et al, 2001a,b;Patiño et al, 2003;McNabb et al, 2004;Bradford et al, 2005;Park et al, 2006), but few have addressed perchlorate's effects on life history characteristics, such as reproductive behaviour (York et al, 2001b(York et al, , 2003Crane et al, 2005). What few studies exist primarily document the number of mounting attempts during mice reproduction (York et al, 2001a) or fertility/fecundity parameters (York et al, 2001b;Wibe et al, 2002;Patiño et al, 2003).…”