Two-day inhalation toxicity study of methyl iodide in the rat

Abstract

The effects of inhaled methyl iodide (MeI) on clinical pathology parameters, glutathione (GSH) tissue levels, serum thyroid hormone and inorganic iodide concentrations, S-methylcysteine hemoglobin concentrations, and liver UDP-glucuronyltransferase activity were studied in the rat. Male rats were exposed by whole-body inhalation to 0, 25, or 100 ppm MeI, 6 h/day for up to 2 days. Serum cholesterol concentrations (both high-density lipoprotein [HDL] and low-density lipoprotein [LDL] fractions) were increased and triglycerides were decreased at both exposure levels. Serum thyroid-stimulating hormone (TSH) concentrations were increased at 25 and 100 ppm, and serum triiodothyronine (T(3)) and thyroxine (T(4)) concentrations were decreased at 100 ppm. There was no change in either reverse triiodothyronine (rT(3)) or UDP-glucuronyltransferase activity at either exposure level. A dose- and time-dependent reduction in GSH levels in blood, kidney, liver, and nasal tissue was observed, with the greatest reduction in nasal tissue (olfactory and respiratory epithelium). MeI exposure also resulted in a substantial dose- and time-dependent increase in both serum inorganic iodide and red blood cell S-methylcysteine hemoglobin adducts. These results indicate that following inhalation exposure, MeI is rapidly metabolized in blood and tissue of rats, resulting in methylation products and release of inorganic iodide.

Iodomethane human health risk characterization

“…These studies are summarized briefly below, and presented in full as stand-alone papers in this issue. An in vivo 2-day inhalation mechanistic toxicity study-rats (Himmelstein et al, 2009). The objective of this study was to evaluate the toxicokinetic behavior of iodomethane in rats exposed by inhalation.…”

“…The hormone changes observed in short-term and chronic rat exposure studies, and the alterations in thyroid weight and histology following chronic exposure, provide unequivocal evidence that iodomethane influences thyroid-pituitary function. The action of iodomethane on the rat thyroid was identified as an effect due to iodide, based (at least in part) on data from the 2-day exposure study in male rats and an understanding of the effects of iodide on thyroid function (Table 7) (Himmelstein et al, 2009). Exposure to iodomethane increases the serum iodide level, and this increase in iodide is known to have a direct action on thyroid function.…”

“…Additional thyroid-pituitary hormone data are available from a 2-day iodomethane exposure study in male rats (Table 6) (Himmelstein et al, 2009). In this study rats were exposed to 25 or 100 ppm iodomethane 6 hours/day for 2 days, and thyroid and pituitary hormone levels were measured 18 hours after the second day of exposure.…”

“…Himmelstein et al (2009) examined the GSH levels in the nasal epithelium at various times during and after iodomethane exposure in rats. Exposure of rats to 25 ppm for 6 hours per day for 2 days resulted in GSH levels that gradually drop during exposure and then rebound when exposure ends, such that GSH levels return to normal levels or greater, 15 hours after exposure ends.…”

Magnetic resonance imaging and computational fluid dynamics (CFD) simulations of rabbit nasal airflows for the development of hybrid CFD/PBPK models

“…In several of these studies, nasal irritation and thyroid effects have been observed in rats and late-term (gestation day [gd] 23–26) resorptions and thyroid effects have been observed in rabbits depending upon the exposure concentration, the duration and/or timing of exposure (Chamberlain et al, 1998; Kirkpatrick, 2002; Himmelstein et al, 2009; Nemec et al, 2009; Sloter et al, 2009). Extrapolations of the portal of entry (nose) and systemic dosimetry of MeI and its metabolite, iodide, can be accomplished using the anatomical and physiological framework from previous hybrid CFD/PBPK models developed for rats and humans.…”