Dose range studies of thallium (i) sulfate subchronic toxicity in perinatally-exposed HSD

Abstract

Thallium (Tl) is a heavy metal that naturally occurs in the earth’s crust. Thallium has been used as a poisoning agent and induces a spectrum of adverse health effects in humans, including alopecia, neurotoxicity, and mortality. Chronic human exposure to thallium compounds occurs due to its presence as a contaminant in drinking water. Currently, there is insufficient toxicological data to support derivation of a human reference dose for thallium compounds. To address this data-gap, the National Toxicology Program (NTP) performed both perinatal rat range-finding and 14-day adult mouse toxicity studies of thallium (I) sulfate. Time-mated SD rats (n=12-20 per group) and offspring were exposed from gestational day 6 (GD 6) to postnatal day 28 (PND 28) via dosed drinking water containing 0, 3.13, 6.25, 12.5, 25, or 50 mg/L thallium (I) sulfate. All 25 and 50 mg/L groups were removed from study by PND 0 due to moribund observations. Thallium exposure concentrations ≤12.5 mg/L did not impact dam fecundity or offspring survivability (PND 4-28), however, whole-body alopecia was observed in all offspring exposed to 12.5 mg/L thallium. Exposure to 12.5 mg/L also resulted in lower PND 28 bodyweights in male (-12%) and female (-9%) offspring, relative to controls. Total thallium concentration in maternal plasma, amniotic fluid (GD 18), fetal homogenate (GD 18), and pup plasma (PND 4) provide evidence of placental and lactational transfer of thallium. Adult B6C3F1 mice (n=5 per sex/group) were exposed for 14 days via dosed drinking water containing 0, 6.25, 12.5, 25, 50, or 100 mg/L thallium (I) sulfate. Observed mortality led to the removal of the 100 mg/L group by study day 9. At study conclusion, mice exposed to 50 mg/L and 25 mg/L displayed -22.5%/-15.9% (males) and -23.3%/-10.7% (females) lower bodyweights relative to controls, respectively. Plasma thallium concentrations ranged from 0.3-2734 ng/mL in male mice and 0.1-1998 ng/mL in female mice. Evidence of thallium toxicity was observed in two rodent species following subchronic drinking water exposure; these results will inform future studies to further characterize thallium hazard and safeguard public health.