Houdini Alert - Ethyl Benzene Carcinogenicity

Toxicological Sciences 2009 107(2):352-366

Mechanism of Ethylbenzene-Induced Mouse-Specific Lung Tumor: Metabolism of Ethylbenzene by Rat, Mouse, and Human Liver and Lung Microsomes


Shakil A. Saghir1, David L. Rick, E. L. McClymont, Fagen Zhang, Michael J. Bartels and James S. Bus
Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674
1 To whom correspondence should be addressed at Toxicology & Environmental Research and Consulting, The Dow Chemical Company, 1803 Building, Midland, MI 48674. Fax: (989) 638-9863. E-mail: ssaghir{at}dow.com

Abstract
This study was conducted to determine species differences in the metabolism of ethylbenzene (EB) in liver and lung. EB (0.22–7.0mM) was incubated with mouse, rat and human liver and lung microsomes and the formation of 1-phenylethanol (1PE), acetophenone (AcPh), 2-ethylphenol (2EP), 4-ethylphenol (4EP), 2,5-ethylquinone, and 3,4-ethylquinone were measured. Reactive metabolites (2,5-dihydroxyethylbenzene-GSH [2EP-GSH] and 3,4-dihydroxyethylbenzene-GSH [4EP-GSH]) were monitored via glutathione (GSH) trapping technique. None of the metabolites were formed at detectable levels in incubations with human lung microsomes. Percent conversion of EB to 1PE ranged from 1% (rat lung; 7.0mM EB) to 58% (mouse lung; 0.22mM EB). More 1PE was formed in mouse lung than in mouse liver microsomes, although formation of 1PE by rat liver and lung microsomes was similar. Metabolism of EB to 1PE was in the order of mouse > rat > human. Formation of AcPh was roughly an order of magnitude lower than 1PE. Conversion of EB to ring-hydroxylated metabolites was much lower (0.0001% [4EP-GSH; rat lung] to 0.6% [2EP-GSH; mouse lung]); 2EP-GSH was typically 10-fold higher than 4EP-GSH. Formation of 2EP-GSH was higher by lung (highest by mouse lung) than liver microsomes and the formation of 2EP-GSH by mouse liver microsomes was higher than rat and human liver microsomes. Increasing concentrations of EB did lead to a decrease in amount of some formed metabolites. This may indicate some level of substrate- or metabolite-mediated inhibition. High concentrations of 2EP and 4EP were incubated with microsomes to further investigate their oxidation to ethylcatechol (ECat) and ethylhydroquinone (EHQ). Conversion of 2EP to EHQ ranged from 6% to 9% by liver (mouse > human > rat) and from 0.1% to 18% by lung microsomes (mouse >> rat >> human). Conversion of 4EP to ECat ranged from 2% to 4% by liver (mouse > human rat) and from 0.3% to 7% by lung microsomes (mouse >> rat >> human). Although ring-oxidized metabolites accounted for a relatively small fraction of overall EB metabolism, its selective elevation in mouse lung microsomes is nonetheless consistent with the hypothesized mode of action for observed preferential toxicity of EB to the lung in this species.

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BrooklynDodger(s) comment: Few employers buy ethyl benzene intentionally, but it constitutes about 1/3 of commercial xylenes, being it weighs the same molecularly. So there's a lot of it around.



IARC classifies EB as 2B: "Ethylbenzene was tested by inhalation exposure in single experiments in mice and rats. In mice, it increased the incidence of lung adenomas in males and of liver adenomas in females. In male rats, it increased the incidence of renal tubule adenomas and carcinomas. An increase in the incidence of renal adenomas was seen in females only after step-sectioning. A study in rats by oral administration could not be evaluated. A metabolite of ethylbenzene, 1-phenylethanol, increased the incidence of renal tubule adenomas in male rats." [Note that IARC considers adenomae as evidence for carcinogenicity, not just carcinomae.]



The renal adenomae in females get EB out of the alpha-2 Houdini machine.



Several volatile organic compounds cause mouse lung tumors but are either less potent or lack this potential in the rat. This gives rise to the Mouse Clara Cell Hypothesis to erase human risk potential, or at least to reduce human potency estimates through parallelogrammation.



The Dodger(s) confess not to have read the full text to determine where in Midland these Dow scientists (Dowagers? some are guys, but a few names are not gender identifiable) got the human lung tissue. Likely from lung biopsies, not usually an indication of good health among donors, and at best a convenience sample not reflecting variation among the human population. [Although, to be fair, neither the lab mouse or rat strains reflect the variation among their species either.]