Covalent binding of styrene and styrene-7,8-oxide to plasma proteins, hemoglobin and dna in the mouse

Nordqvist, Marianne; Löf, Agneta; Osterman-Golkar, Siv; Walles, Solveig

doi:10.1016/s0009-2797(85)80120-4

Cited by 46 publications

(20 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Oxidative metabolism of olefinic double bonds to the epoxide by cytochrome P450 is recognized as a critical determinant to the toxic responses and to the metabolic fate of vinyl compounds. Styrene-7,8-epoxide is the reactive metabolite of styrene (Nordqvist et al, 1985) and the corresponding epoxides of DVB are likely the toxic metabolites of this chemical. Divinylbenzene may be more reactive and toxic than styrene because it can potentially be metabolized to either an epoxide or a diepoxide {meta and para).…”

Section: Discussionmentioning

confidence: 99%

Toxicity of Divinylbenzene-55 for B6C3F1 Mice in a Two-Week Inhalation Study

Morgan¹,

Mahler²,

Wilson³

et al. 1997

Toxicol Sci

View full text Add to dashboard Cite

Divinylbenzene (DVB) is a crosslinking monomer used primarily for copolymerization with styrene to produce ion-exchange resins. The toxicity of inhaled DVB was investigated because of the potential for worker exposure and the structural similarity of DVB to styrene, a potential carcinogen. Male and female B6C3F1 mice were exposed to 0, 25, 50, or 75 ppm DVB for 6 hr/day, 5 days/week for up to 2 weeks. Six mice/sex/dose group were killed after 3, 5, and 10 exposures and six mice/sex in the 75 ppm group were killed 7 days after 10 exposures. The most severe effects occurred in the nasal cavity and liver, with less severe effects occurring in the kidneys. In the nasal cavity olfactory epithelium acute necrosis and inflammation were present at early time points followed by regeneration, architectural reorganization, and focal respiratory metaplasia by 7 days after the last exposure. Olfactory epithelial changes were concentration-dependent with extensive involvement at 75 ppm and peripheral sparing at 25 ppm. There was also necrosis and regeneration of olfactory-associated Bowman's glands as well as the lateral nasal (Steno's) glands. Hepatocellular centrilobular (CL) necrosis was observed only in the 75 ppm dose group and was similar to that caused by styrene. A time-dependent progression was observed, characterized by CL degeneration after 1 exposure, necrosis after 3 and 5 exposures, and chronic inflammation with CL karyomegaly after 10 exposures and 7 days after the 10th exposure. Hepatic GSH levels were decreased in a dose-dependent manner. In the kidneys, transient tubular damage was observed in some male mice exposed to 75 ppm, and appeared to be a response to DVB-induced tubular epithelial injury. Divinylbenzene (DVB; CAS No. 1321-74-0) is a specialty monomer used for producing vinyl polymers. The toxicity of inhaled DVB was investigated because of the potential for worker exposure and the structural similarity of DVB to styrene, a potential human carcinogen (IARC, 1987). The bifunctionality conferred by the two vinyl groups makes DVB a highly reactive crosslinking agent and may also contribute to its toxicity. Occupational exposure to DVB occurs primarily by inhalation and dermal contact and consequently DVB is an irritant to the eyes and respiratory system (Clayton and Clayton, 1981). The current Occupational Safety and Health Administration threshold limit value (8-hr timeweighted average) for DVB is 10 ppm (ACGLH, 1994).Divinylbenzene monomer is manufactured by dehydrogenation of mixed isomeric diethylbenzenes. After removal of light by-products, the product is recovered as a mixture of m-and /?-DVB and m-and /7-ethylvinylbenzene (EVB), the partial dehydrogenation product. Because the DVB monomer readily polymerizes to a brittle, insoluble resin, it is heavily inhibited with tert-butyl catechol and diluted with EVB to minimize this reaction. Three commercial grades of DVB are produced containing approximately 22% (DVB-22), 55% (DVB-55), and 80% (DVB-80) DVB.By far, the greatest use of DVB is as a cross-l...

show abstract

Section: Discussionmentioning

confidence: 99%

Toxicity of Divinylbenzene-55 for B6C3F1 Mice in a Two-Week Inhalation Study

Morgan¹,

Mahler²,

Wilson³

et al. 1997

Toxicol Sci

View full text Add to dashboard Cite

show abstract

“…In view of our success at detecting hydroxyethyl adducts, we have recently devised methods for monitoring phenylhydroxyethyl adducts that would be derived from exposure to styrene oxide (21).…”

Section: Phenylhydroxyethylmentioning

confidence: 99%

Identification of endogenous electrophiles by means of mass spectrometric determination of protein and DNA adducts.

Farmer

Bailey

Naylor

et al. 1993

Environ Health Perspect

View full text Add to dashboard Cite

Monitoring exposure to alkylating agents may be achieved by quantitatively determining the adduct levels formed with nucleic acids and/or proteins. One of the most significant results arising from the application of this approach has been the discovery in control populations of "background" levels of alkylated nudeic acid bases or alkylated proteins, in particular hemoglobin (Hb). In the case of Hb, a wide variety ofsuch adducts have been detected and quantitated by mass spectrometric techniques, with methylated, 2-carboxyethylated, and 2-hydroxyethylated modifications being most abundant. Although the source of these alkylation products is unknown, both endogenous and exogenous sources may be proposed. We have recently confirmed the presence of the N-terminal hydroxyethylvaline adduct in control human Hb using tandem mass spectrometry (MS-MS) and have now established background levels using GC-MS in more than 70 samples. Smoking raises the levels of the adduct up to 10-fold and occupational exposure to ethylene oxide up to 300-fold.Background levels of alkylated nucleic acids may be studied by analysis ofN7-alkylated guanine or N3-alkylated adenine, which are excised from nucleic acids after their formation and are excreted in urine. Although the presence of some of these urinary constituents may be accounted for by their natural occurrence in RNA or diet, the endogenous or exogenous source ofothers is unknown. Quantitative methods using MS-MS have now been developed for five ofthe observed urinary alkylguanines [N7-methyl-, N2-methyl-, N2-dimethyl-, N7-(2-hydroxyethyl)-, and N2-ethylguanine]. A GC-MS method has also been developed to measure urinary thymine glycol as a possible monitor of oxidative DNA damage.

show abstract

“…In vivo, only one publication reports on the identification of a guanyl-7 adduct in liver DNA isolated from mice after i.p. administration of tritiated SO (8). A quantitative analysis of the overall DNA-binding potency of SO is not possible, however, on the basis of tfifese results.…”

Section: Introductionmentioning

confidence: 99%

Investigation of the covalent binding of styrene-7,8-oxide to DNA in rat and mouse

Cantoreggi

Lutz

1992

Carcinogenesis

View full text Add to dashboard Cite

Styrene-7,8-oxide (SO), the main intermediate metabolite of styrene, induces hyperkeratosis and tumors in the forestomach of rats and mice upon chronic administration by gavage. The aim of this study was to investigate whether DNA binding could be responsible for the carcinogenic effect observed. [7?H]SO was administered by oral gavage in corn oil to male CD rats at two dose levels (1.65 or 240 mg/kg). After 4 or 24 h, forestomach, glandular stomach and liver were excised, DNA was isolated and its radioactivity determined. At the 4 h time point, the DNA radioactivity was below the limit of detection in the forestomach and the liver. Expressed in the units of the covalent binding index, CBI = (/unol adduct/mol DNA nucleotide)/(mmol chemical administered/kg body wt), the DNA-binding potency was below 2.6 and 2.0 respectively. In the glandular stomach at 4 h, and in most 24 h samples, DNA was slightly radiolabeled. Enzymatic degradation of the DNA and separation by HPLC of the normal nucleotides showed that the DNA radioactivity represented biosynthetic incorporation of radiolabel into newly synthesized DNA. The limit of detection of DNA adducts in the glandular stomach was 1.0. In a second experiment, [T-TIISO was administered by i.p. injection to male B6C3F1 mice. Liver DNA was analyzed after 2 h. No radioactivity was detectable at a limit of detection of CBI < 0.6. In agreement with the relatively long half-life of SO in animals, the chemical reactivity of SO appears to be too low to result in a detectable production of DNA adducts in an in vivo situation. Upon comparison with the DNA-binding of other carcinogens, a purely genotoxic mechanism of tumorigenic action of SO is unlikely. The observed tumorigenic potency in the forestomach could be the result of strong tumor promotion by high-dose cytotoxkity followed by regenerative hyperplasia.

show abstract

Covalent binding of styrene and styrene-7,8-oxide to plasma proteins, hemoglobin and dna in the mouse

Cited by 46 publications

References 23 publications

Toxicity of Divinylbenzene-55 for B6C3F1 Mice in a Two-Week Inhalation Study

Toxicity of Divinylbenzene-55 for B6C3F1 Mice in a Two-Week Inhalation Study

Identification of endogenous electrophiles by means of mass spectrometric determination of protein and DNA adducts.

Investigation of the covalent binding of styrene-7,8-oxide to DNA in rat and mouse

Contact Info

Product

Resources

About