What is the biological significance of the changes in cis and trans ratio noted at higher levels of exposure?

1,3-D, which is available as soil fumigant for preplant treatment of soil to control parasitic nematodes and manage soil borne diseases consists of both cis- and trans- isomers at approximately equal levels. It was shown that the ratio of cis/trans 1,3-D isomers changes substantially from ~0.13 to ~0.20 between the exposure concentrations of 40 and 60 ppm. Shifts in the ratio of cis and trans 1,3-D also support nonlinear TK well below 60 ppm. In contrast, the cis/trans ratios following acute exposures had a change from 0.11 to 0.23 between air levels of 60 and 150 ppm (US EPA 2017)
The cis- and trans-isomers are substrates for hepatic glutathione- S-alkyl transferase, forming mercapturic acids, which are excreted in the urine. The trans-isomer is conjugated 4-5 times more slowly than the cis-isomer. The principal urinary metabolite in rats and mice is N-acetyl- S-(3-chloroprop-2-enyl) L-cysteine; this compound can be used for biological monitoring in humans. A second, minor metabolic pathway has been identified for the cis-isomer that involves mono-oxygenation to cis-1,3-dichloropropene oxide, which can also be conjugated with glutathione. The high proportion of the trans-isomer that occurs in expired air results from an alternative metabolic pathway to conjugation that has a higher specificity for the trans- than for the cis-isomer (http://www.inchem.org/documents/ehc/ehc/ehc146.htm).
Yang (1989) reported that Clearance (CL) of both isomers of 1,3-D in rats at 100 ppm exposure was comparable; at 300 rpm the trans-form had higher CL (due to saturable process) than that of cis-form (linear process) and at 500 rpm the cis form had greater CL (both forms cleared by saturable process). It was also suggested that cis -13D is more active as an alkylating agent than the Trans-1,3D since the Cis-form favors cation stabilization due to steric hindrances and neighboring effects of the choline atoms (Neudecker et al., 1980).

Changes in the relative ratio of the cis and trans isomers at the highest exposures may indicate that the glutathione-dependent metabolism of 1,3-D of one isomer is facilitated compared to the other isomer (i.e., they could have two different Km values for the affinity to the enzyme), which becomes evident at saturation while the metabolic activity becomes more limited (i.e., when the competition between the two isomers is maximal in the non-linear area). Hence, at a limited metabolic activity at saturation combined with a difference in affinity (Km) could highlight which isomer is the most metabolised by the Glutathione apparently. At saturation (non-linear area), it might become important to define which of the isomer is the most toxic since one isomer may accumulate more than the other in the non-linear area. Based on Figure 5, a KMD of 10 ppm should cover both isomers at the starting point of the non-linearity effect (saturation).

This could very well be explained by an enzyme saturation. If the Km of the cis is different than the trans 1,3-D, there would be a shift in ratio of intrinsic clearance at levels higher than the lowest Km and hence the ratio. The hypothesis of cofactor depletion cannot explain this phenomenon.