Do you agree that the inhalation study of Yang (1989; see pages 75-76 of the pdf), showing increased 1,3-D blood levels in rat after diethylmaleate treatment, would correlate with the GSH depletion and non-dose proportional increases in 1,3-D blood levels seen in mice after single or repeated inhalation exposures? (please explain)

Diethylmaleate (DEM) is known to decrease GSH levels in various organs by enzymatic conjugation with reduced GSH catalyzed by GSH transferase. Depletion of GSH by DEM therefore would spare1,3-D conjugation thus resulting in non-dose proportional increase in 1,3-D blood levels in mice after single/multiple dose exposures.

The results in that document are generally what would be expected if GSH was depleted by DEM.

DEM is known to deplete GSH levels. GSH depletion is a plausible explanation for non-dose proportional increases in 1,3-D blood levels seen in mice, but not the only plausible mechanism as mentioned above.

Diethylmaleate (DEM) decreases glutathione (GSH) levels in various organs by enzymatic conjugation with reduced GSH catalyzed by GSH transferase (e.g., Deneke et al, J. Appl. Physiol.; 1985). Therefore, Diethylmaleate is a well know compound that is eliminated via GSH and have affinity for the GSH higher than several other compounds. Therefore, it seems that we are in a condition of chemical-chemical interactions, where the Diethylmaleate depleted the GSH probably more than 1,3-D; hence the GSH depletion was greater than expected for 1,3-D in the presence of Diethylmaleate. Consequently, the blood levels of 1,3-D were superior in the presence of 1,3-D compared to its absence (control). This may again suggest that 1,3-D is eliminated via the GSH metabolic pathway, and, hence, would correlate with the GSH depletion and non-dose proportional increases in 1,3-D blood levels seen in mice after single or repeated inhalation exposures. The study of Yang et al. has been conducted in the rat, whereas the study of Dow has been made in mice. However, as said in the white paper, the ADME of 1,3-D was consistent across the preclinical species and human.