Evaluation of possible modes of action for acute effects of methyl iodide in laboratory animals

Recent studies have indicated that exposures to methyl iodide (Mel) produce a number of effects in laboratory animals, including fetal toxicity, neurotoxicity, and degeneration of the nasal epithelium. An understanding of the mode of action by which the effects of Mel are produced is useful in guiding critical decisions used in risk assessment. These decisions include the selection of the appropriate internal dose measure(s) calculated using physiologically based pharmacokinetic (PBPK) modeling, and evaluating the relevance of the observations in animals to human health. Modified Hill criteria were used to evaluate several possible mode(s) of action through which Mel produces toxicity in animals. For each endpoint, the key studies were summarized and several possible modes of action were compared to the modified Hill criteria. The available data best support the hypothesis that the fetal effects were likely associated with modulation of the thyroid hormones by iodide during development. This mode of action dictates the use of an internal dose measure in the risk assessment that is indicative of fetal iodide status, such as cumulative iodide concentration (area-under-the-curve or AUC) for iodide in fetal blood. The acute transient neurotoxicity observed in rats exposed to Mel is best supported by a mode of action involving modification of ion currents by the parent chemical in nerve cells. In the case of assessing the potential acute neurotoxicity of Mel, the peak concentration of Mel in the brain would be the appropriate internal dose measure. Finally, the nasal lesions associated with exposure to high concentrations of Mel in rats are best supported by a mode of action that involves glutathione (GSH) depletion in the nasal epithelial tissue. The daily minimum GSH level in olfactory epithelium is the most appropriate internal dose measure for use in risk assessment for this endpoint. Confidence in these modes of action is considered low for the neurotoxic effects, medium for the nasal effects, and high for the fetal effects.