A weight of evidence review on the mode of action, adversity, and the human relevance of xylene's observed thyroid effects in rats.

Xylene substances have wide industrial and consumer uses and are currently undergoing dossier and substance evaluation under Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) for further toxicological testing including consideration of an additional neurotoxicological testing cohort to an extended one-generation reproduction toxicity (EOGRT) study. New repeated dose study data on xylenes identify the thyroid as a potential target tissue, and therefore a weight of evidence review is provided to investigate whether or not xylene-mediated changes on the hypothalamus-pituitary-thyroid (HPT) axis are secondary to liver enzymatic induction and are of a magnitude that is relevant for neurological human health concerns. Multiple published studies confirm xylene-mediated increases in liver weight, hepatocellular hypertrophy, and liver enzymatic induction the oral or inhalation routes, including an increase in uridine 5'-diphospho-glucuronosyltransferase (UDP-GT) activity, the key step in thyroid hormone metabolism in rodents.

Comparative evaluation of rat and human in vitro assays for evaluation of thyroid toxicity.

The effects of ten test chemicals towards thyroid sodium-iodide symporter (NIS), thyroid peroxidase (TPO), and deiodinases (DIOs) type I, II, and III were evaluated in in vitro rat and human systems and compared. Test chemicals known to directly affect TH levels in vivo were confirmed to effectively inhibit at least one of the tested in vitro endpoints, without significant disparities between species, and the tested compounds known to not affect thyroid function, were found ineffective. Interestingly, Iodide Transport Blocker 5, a potent non-competitive iodine uptake inhibitor, exhibited effects beyond direct NIS inhibition, by impacting NIS function through ATP depletion, and also inhibited TPO and DIO1/2 enzymes, although to a lesser extent.

Xylene: weight of evidence approach case study to determine the need for an extended one generation reproductive study with a developmental neurotoxicity animal cohort.

Xylene is a high production volume chemical that is widely used as a solvent and polymer precursor, and is currently undergoing substance evaluation under Registration, Evaluation, Authorization and Restriction of Chemicals (REACH). Xylenes recently received testing decisions on one-generation reproductive toxicity (EOGRT) studies with additional developmental neurotoxicity (DNT) cohorts for each of the three isomers. Xylene presents a unique opportunity to investigate the need for additional animal DNT toxicology testing because it is a legacy industrial chemical for which a significant amount of animal and human data already exists on its toxicity profile, including central nervous system effects.