Toxicokinetic interaction of 2,5-hexanedione and methyl ethyl ketone

Yu, Rong Chun; Hattis, Dale; Landaw, Elliot M.; Froines, John R.

doi:10.1007/s00204-001-0298-2

Cited by 8 publications

(2 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Analysis of serum samples from subjects with and without diabetes mellitus revealed similar qualitative profiles of volatile metabolites (low nanogram concentration), with relatively high and low concentrations respectively of 2-hexanone and 3-heptanone, both of can undergo ω-oxidation to form γ-diketones, namely 2,5-hexanedione and 3,6-heptanedione [ 87 , 88 ]. Normal and diabetic sera contained similar concentrations of 2-butanone (methyl ethyl ketone), a compound that increases the persistence of blood-borne 2,5-hexanedione and markedly potentiates the neurotoxic potency of n -hexane and 2-hexanone [ 135 , 136 , 137 ]. Other aliphatic ketones found in normal and diabetic serum include 2-propanone, 2-pentanone, 4-heptanone, and 2-octanone [ 85 ].…”

Section: Relationship To Neuropathies Of Endogenous Originmentioning

confidence: 99%

The Role of Protein Adduction in Toxic Neuropathies of Exogenous and Endogenous Origin

Spencer

Chen

2021

Toxics

View full text Add to dashboard Cite

The peripheral (axonal) neuropathy associated with repeated exposure to aliphatic and aromatic solvents that form protein-reactive γ-diketones shares some clinical and neuropathological features with certain metabolic neuropathies, including type-II diabetic neuropathy and uremic neuropathy, and with the largely sub-clinical nerve damage associated with old age. These conditions may be linked by metabolites that adduct and cross-link neuroproteins required for the maintenance of axonal transport and nerve fiber integrity in the peripheral and central nervous system.

show abstract

Section: Relationship To Neuropathies Of Endogenous Originmentioning

confidence: 99%

The Role of Protein Adduction in Toxic Neuropathies of Exogenous and Endogenous Origin

Spencer

Chen

2021

Toxics

View full text Add to dashboard Cite

show abstract

“…107 Also present in similar concentrations in normal and diabetic sera was 2-butanone (methyl ethyl ketone), a compound that potentiates the neurotoxic potency of n-hexane and 2-hexanone. [108][109][110][111] Since degenerative nerve fiber changes with the advance of aging resemble those seen in the early stages of distal axonopathies, 112 and central-peripheral axonopathy underpins type 2 diabetic neuropathy, 71 it will be important to determine the origin of g-diketones and precursors with neurotoxic potential in normal subjects and whether they contribute to nerve fiber changes in aged subjects and those with diabetic neuropathy.…”

Section: Later Cns Protein Changesmentioning

confidence: 99%

Neuroprotein Targets of γ-Diketone Metabolites of Aliphatic and Aromatic Solvents That Induce Central–Peripheral Axonopathy

Spencer

2020

Toxicol Pathol

View full text Add to dashboard Cite

Peripheral neuropathy associated with chronic occupational and deliberate overexposure to neurotoxic organic solvents results from axonal degeneration in the central and peripheral nervous system. Human and experimental studies show that axonopathy is triggered by the action of neuroprotein-reactive γ-diketone metabolites formed from exposure to certain aliphatic solvents ( n-hexane, 2-hexanone) and aromatic compounds (1,2-diethylbenzene, 1,2-4-triethylbenzene, 6-acetyl-1,1,4,4-tetramethyl-7-ethyl-1,2,3,4-tetralin). Neuroprotein susceptibility is related primarily to their differential content of lysine, the ∊-amino group of which is targeted by γ-diketones. Specific neuroprotein targets have been identified, and the sequence of molecular mechanisms leading to axonal pathology has been illuminated. While occupational n-hexane neuropathy continues to be reported, lessons learned from its experimental study may have relevance to other causes of peripheral neuropathy, including those associated with aging and diabetes mellitus.

show abstract

Diethylbenzol (alle Isomere) [MAK Value Documentation in German language, 2018]

Hartwig

Arand²

2018

The MAK‐Collection for Occupational Health and Safety

View full text Add to dashboard Cite

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has evaluated diethylbenzene as mixture of isomers [ 25340‐17‐4 ], as well as the individual isomers 1,2‐diethylbenzene [ 135‐01‐3 ], 1,3‐diethylbenzene [ 141‐93‐5 ] and 1,4‐diethylbenzene [ 105‐05‐5 ] considering all toxicological endpoints. Available publications and unpublished studies are described in detail. 1,2‐Diethylbenzene is the most toxic of the isomers, the critical effect being peripheral neurotoxicity which is due to a gamma‐diketone formed metabolically. In subchronic inhalation and oral studies in rats with diethylbenzene mixtures containing 1,2‐diethylbenzene, subclinical neurotoxicity is observed at all concentrations and doses used. From these studies a maximum concentration at the workplace (MAK value) of 1 ml/m 3 is set for 1,2‐diethylbenzene. For a diethylbenzene mixture containing 10 % 1,2‐diethylbenzene, the critical effect in rats is leuco‐ and lymphopenia. A MAK value of 5 ml/m 3 is set for diethylbenzene mixtures and the MAK value for 1,2‐diethylbenzene has to be observed additionally. In rats, critical endpoints for 1,3‐diethylbenzene are increased liver and thyroid weight and for 1,4‐diethylbenzene altered clinical chemical parameters and increased kidney weight. A MAK value of 5 ml/m 3 for both isomers is derived. Since systemic effects are critical, Peak Limitation Category II is designated for all isomers. As peripheral neurotoxicity is a cumulative effect, an excursion factor of 8 is set for 1,2‐diethylbenzene. The default excursion factor of 2 for systemically acting substances is set for diethylbenzene mixtures as well as 1,3‐ diethylbenzene and 1,4‐diethylbenzene as their half‐lives are not known. Thus, the allowable peak exposures are lower than those of other alkyl benzenes and also prevent from irritation. By analogy with acrylamide it is deduced that rats exposed in utero to 1,2‐diethylbenzene are not more susceptible to peripheral neurotoxicity than adult animals. The oral NOAEL for developmental toxicity of 1,2‐diethylbenzene in rats is scaled to a concentration of 17 ml/m 3 at the workplace. Therefore, damage to the embryo or foetus is unlikely when the MAK value is observed and 1,2‐diethylbenzene is assigned to Pregnancy Risk Group C. The oral NOAEL for developmental toxicity of a diethylbenzene mixture in rats is scaled to a concentration of 94 ml/m 3 at the workplace. Developmental toxicity studies with 1,3‐diethylbenzene and 1,4‐diethylbenzene are lacking, however, these isomers are contained in the diethylbenzene mixture to about 60 % and 30 %, respectively. Therefore, damage to the embryo or foetus is unlikely when the MAK value is observed and diethylbenzene mixtures as well as 1,3‐diethylbenzene and 1,4‐diethylbenzene are assigned to Pregnancy Risk Group C. Diethylbenzenes are not genotoxic in vitro and in vivo. In a carcinogenicity study dermal application of a diethylbenzene mixture induced a single squamous carcinoma in mice, which is judged not sufficient for classification as a carcinogen. According to skin absorption models, percutaneous absorption can contribute significantly to systemic toxicity and all diethylbenzene isomers are designated with an “H” notation. Limited data show no sensitization.

show abstract

Toxicokinetic interaction of 2,5-hexanedione and methyl ethyl ketone

Cited by 8 publications

References 42 publications

The Role of Protein Adduction in Toxic Neuropathies of Exogenous and Endogenous Origin

The Role of Protein Adduction in Toxic Neuropathies of Exogenous and Endogenous Origin

Neuroprotein Targets of γ-Diketone Metabolites of Aliphatic and Aromatic Solvents That Induce Central–Peripheral Axonopathy

Diethylbenzol (alle Isomere) [MAK Value Documentation in German language, 2018]

Contact Info

Product

Resources

About