Check out our New Publishers' Select for Free Articles

Archives of Toxicology (v.83, #12)

EU research activities in alternative testing strategies: current status and future perspectives by T. Vanhaecke; S. Snykers; V. Rogiers; B. Garthoff; J. V. Castell; J. G. Hengstler (pp. 1037-1042).

Estimation of human maximum tolerable intake for methylmercury based on two recent studies in monkeys by Ryoji Yamamoto; Masayuki Shima (pp. 1043-1048).

Results of long-term toxicity studies of methylmercury (MeHg) in monkeys have been reported. The aim of this study was to estimate the threshold body burden, blood level and threshold daily intake (TDI) of MeHg for monkey and human. The concepts of this study stood on that body burden of MeHg would follow the accumulation theory, and that the more intake of MeHg, the earlier the neurotoxicity appeared, vice versa. The threshold blood level (TBL) of monkey was estimated to be 0.71 as Hg mg/L and the body burden was estimated to be 4.83 as Hg mg/kg. The TDI was estimated to be 0.025 as Hg mg/kg day. In human, the TBL was estimated with compensation by elimination constants of human and monkey. The blood threshold limit and TDI of human were estimated to be 0.33 as Hg mg/L and 0.0046 as Hg mg/kg day, respectively. The estimated body burden was 0.46 as Hg mg/kg.

Keywords: Methylmercury; Body burden; Human; Monkey; Threshold blood level; Maximum tolerable daily intake; One-compartment

Feasibility study to support a threshold of sensitization concern concept in risk assessment based on human data by Detlef Keller; Matthias Krauledat; Julia Scheel (pp. 1049-1060).

In analogy to the Threshold of Toxicological Concern concept, a Threshold of Sensitization Concern (TSC) concept is proposed for chemicals with respect to their ability to induce an allergic contact dermatitis. Recently, the derivation of a dermal sensitization threshold was suggested based on an evaluation of animal data. In order to establish the concept with human data, we conducted a meta-analysis taking into account No Expected Sensitization Induction Levels for fragrance ingredients from the IFRA/RIFM dataset. Based on a statistical analysis by applying Sensitization Assessment Factors that account for interindividual variability and different exposure conditions, TSC values of 0.91 or 0.30 μg/cm² can be derived in terms of amount per skin area. TSC values are compared with typical exposure levels of cosmetic products. A substance can be considered to be virtually safe if the quotient of exposure level and TSC is <1. The findings derived from human data include several conservative assumptions and largely support the dermal sensitization thresholds previously derived from animal data. The TSC concept might in principle be used for any untested chemical and therefore help in some cases to waive animal testing.

Keywords: Dermal sensitization; Quantitative risk assessment; Fragrance ingredients; Threshold; TTC

Driving gradual endogenous c-myc overexpression by flow-sorting: intracellular signaling and tumor cell phenotype correlate with oncogene expression by Kasper Jermiin Knudsen; Gitte-Mai Nelander Holm; Jonas S. Krabbe; Nicolai Listov-Saabye; Benedicte Kiehr; Martin Dufva; Jette E. Svendsen; Martin B. Oleksiewicz (pp. 1061-1074).

Insulin-exposed rat mammary cancer cells were flow sorted based on a c-myc reporter plasmid encoding a destabilized green fluorescent protein. Sorted cells exhibited gradual increases in c-myc levels. Cells overexpressing c-myc by only 10% exhibited phenotypic changes attributable to c-myc overexpression, such as cell cycle disturbances, increased cell size, and overexpression of the S6 ribosomal protein. Cells overexpressing c-myc by 70% exhibited additional phenotypic changes typical of c-myc overexpression, such as increased histone H3 phosphorylation, and reduced adherence. Sorted cells also exhibited overexpression of the IGF-1R, and slightly elevated expression of the IR. Increased susceptibility to the mitogenic effect of insulin was seen in a small proportion of the sorted cells, and insulin was more effective in activating the p44/42 MAPK pathway, but not the PI3K pathway, in the sorted cells than in the nonsorted cell population. To our knowledge, this is the first in vitro system allowing functional coupling between mitogenic signaling by a well-defined growth factor and gradual overexpression of the normal, endogenous c-myc gene. Thus, our flow-sorting approach provides an alternative modeling of the receptor-mediated carcinogenic process, compared to the currently used approaches of recombinant constitutive or conditional overexpression of oncogenic transmembrane receptor tyrosine kinases or oncogenic transcription factors.

Keywords: Preclinical carcinogenicity safety assessment; Molecular toxicology; Green fluorescent protein; Insulin mitogenicity; c-myc; Fluorescence-activated cell sorting

Ethanol and liver: recent advances in the mechanisms of ethanol-induced hepatosteatosis by Tao Zeng; Ke-Qin Xie (pp. 1075-1081).

Ethanol-induced fatty liver is a worldwide health problem without effective therapeutic methods. The underlying mechanisms are extremely complex and not fully understood. The hepatosteatosis caused by ethanol can be attributed to many factors, including the changes of the redox condition, transportation impairment of the synthesized lipid, inhibition of fatty acid oxidation, and the enhancement of the lipogenesis. Recent studies focus on the reduced oxidation of fatty acid and the enhancement of the do novo lipogenesis, and several factors are sequentially revealed. Two important nuclear transcription factors, peroxisome proliferators-activated receptor α (PPARα) and sterol regulatory element binding protein-1 (SREBP-1), and the lipid metabolism-associated enzymes regulated by the two molecules, are shown to be involved in ethanol-induced steatosis. The AMP-dependent protein kinase, adiponectin, and tumor necrosis factor α (TNF-α) may mediate the modulation of ethanol on PPARα and SREBP-1. In addition, a number of studies demonstrate that plasminogen activator inhibitor-1 (PAI-1) is also involved in ethanol-induced fatty liver, and its effects may be associated with the TNF-α production. Furthermore, the role of CYP2E1 has also been investigated. Some studies showed that CYP2E1 played a critical role in the development of alcoholic fatty liver, which was denied by other reports. As such, the exact role of CYP2E1 needs to be further studied.

Keywords: Ethanol; PPARα; SREBP-1; AMPK; TNF-α; PAI-1; CYP2E1

Effects of 4-pyridine aldoxime on nerve agent-inhibited acetylcholinesterase activity in guinea pigs by Tsung-Ming Shih; Jacob W. Skovira; John H. McDonough (pp. 1083-1089).

Methoxime (MMB-4) is a leading candidate oxime acetylcholinesterase (AChE) reactivator to replace pralidoxime (2-PAM) for therapeutic treatment of nerve agent intoxication. 4-Pyridine aldoxime (4-PA) is a synthetic starting material, a breakdown product, and a probable metabolite of MMB-4. There is a possibility that 4-PA may adversely interact with the nerve agent, thereby affecting nerve agent toxicity and biological AChE activity. This study evaluated the effects of 4-PA on sarin (GB)-, cyclosarin (GF)-, and VX-induced toxicity and AChE activity in blood, brain, and peripheral tissues of guinea pigs. Animals were pretreated with atropine methyl nitrate (1.0 mg/kg, im) 15 min prior to subcutaneous administration with 1.0× LD₅₀ of GB, GF, or VX and then treated 15 min after the administration of nerve agents with 4-PA (3.5, 7.0, or 14.0 mg/kg, im). The dose–response effects of 4-PA alone were also examined. Toxic signs and lethality were monitored, blood and tissues were collected, and AChE activities were determined at 60 min after nerve agent administration. Under the condition of this study, all animals exposed to nerve agents exhibited some degree of toxic signs such as salivation, lacrimation, rhinorrhea, and convulsions. 4-PA at the three doses tested neither induced toxic signs nor altered the toxicity of GB, GF, or VX at the 1.0× LD₅₀ exposure dose. Additionally, it did not modify the AChE activity in blood, brain, and peripheral tissues by itself or affect the AChE activity inhibited by a 1.0× LD₅₀ dose of these three nerve agents in guinea pigs.

Keywords: Acetylcholinesterase; Cholinesterase; Cyclosarin; Guinea pig; Methoxime; Organophosphorus compounds; Oximes; Pralidoxime; 4-Pyridine aldoxime; Sarin; VX

Comparative antidotal efficacy of benzylpenicillin, ceftazidime and rifamycin in cultured human hepatocytes intoxicated with α-amanitin by Jan Magdalan; Alina Ostrowska; Aleksandra Piotrowska; Agnieszka Gomułkiewicz; Adam Szeląg; Piotr Dzięgiel (pp. 1091-1096).

The most often used antidote to treat poisoning caused by amanitin-containing mushrooms is benzylpenicillin (BPCN). However, a very few reports suggest that other antibiotics such as ceftazidime (CEFT) and rifamycin SV (RIFSV) show better antidote activity against amanitins than BPCN. Given this, there is an ongoing debate as which of three antidotes is optimal for treatment of such poisonings. In this study, the efficacy of BPCN was compared with those of CEFT and RIFSV in human hepatocyte model. The functional integrity and viability of cultured hepatocytes was evaluated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay and by measurements of lactic dehydrogenase (LDH) activity. In the first experimental layout, hepatocytes were simultaneously exposed to α-AMA and tested antidotes, while in the second layout, the cells were exposed for the first 12 h to α-AMA only, and then, the medium containing α-AMA was exchanged to culture medium containing both α-AMA and the antidotes tested. The results demonstrated that simultaneous administration of α-AMA and each of tested antidotes (BPCN, CEFT, RIFSV) effectively protected human hepatocytes; however, in the group dosed with BPCN, the highest hepatocyte viability was observed. In cell cultures from experimental layout II, all tested antidotes were ineffective, which indicates that after the critical dose of α-AMA had been taken up by hepatocytes, further suppression of this process does not protect the cells against injury. Thus, 12 h of exposure of incubated hepatocytes to α-AMA is a sufficient time for such a cellular uptake of a critical dose of this toxin. In summary, it can be concluded that easily accessible and low-cost BPCN should be widely used as an antidote against amanitins. However, the key to successful therapy is a quick implementation of an antidote in order to protect as large as possible portion of the liver parenchyma against the devastating uptake of a critical dose of amanitins.

Keywords: α-Amanitin; Human hepatocytes; Intoxication; Benzylpenicillin; Ceftazidime; Rifamycin

Effects of synthetic para-nonylphenol isomers administered chronically throughout pregnancy and lactation on reproductive system of mouse pups by Tamio Sato; Hiroaki Saito; Taketo Uchiyama; Yasuo Fujimoto; Takao Katase; Osamu Kai (pp. 1097-1108).

The aim of this study was to analyze the effects of synthetic para-nonylphenol isomers administered chronically throughout pregnancy and lactation on the reproductive system of mouse pups. The two synthetic isomers used in this study showed higher (3E22NP) or lower (44NP) estrogen receptor (ER) binding activity on in vitro yeast assay than a commercial NP (NPmix). Female mice were implanted with a tube filled with one of three NPs and estradiol-17β (E2) before mating. The tube was kept in the mice throughout pregnancy and lactation period, until their pups had weaned at 28 days of age (PND 28). The data indicated that in males, NPs decreased body weight in some dose groups on PND28 and increased weights of testes and epididymides. However, the rate of seminiferous tubules having elongate spermatids (steps10–16) decreased significantly in NPs and E2 treated groups, except for the 44NP groups. In female mice, NPs and E2 increased weights of ovaries, uterus and vagina in the pups in some dose groups on PND 28. However, there were no differences in the day of vaginal opening and numbers of corpus lutea. The present study demonstrates that the effects of these two isomers of NP on the pup reproduction at PND 28 are not quite different, despite them showing different levels of ER binding activity using in vitro yeast assay.

Keywords: Synthetic p-nonylphenol; Isomer; Mice; Long term administration; Pregnancy; Lactation; Pup reproduction

Quantitative determination of TEGDMA, BHT, and DMABEE in eluates from polymerized resin-based dental restorative materials by use of GC/MS by Mario Seiss; Christopher Langer; Reinhard Hickel; Franz-Xaver Reichl (pp. 1109-1115).

This study investigated the leaching of ingredients from several commercial dental composite resins cured with LED, and immersed in methanol or water for 24 h, respectively. The composites used were: Admira Dentin (VOCO), Artemis Schmelz (Enamel) (Ivoclar Vivadent), Els extra low shrinkage (Saremco Dental), Filtek Supreme XT Dentin (3 M ESPE), Gradia Direct (GC), Venus & Venus flow (Heraeus Kulzer), and XRV Herculite Prodigy Enamel (Kerr). From each dental composite four specimens with defined structure and 100-mg net weight were made. After the polymerization process, according to manufacturer's instructions, the specimens were immersed in either 1 ml water or 1 ml methanol and incubated at 37°C for 24 h. Eluted ingredients triethyleneglycoldimethacrylate (TEGDMA), 2,6-di-tert-butyl-4-methylphenol (BHT), and 4-N,N-dimethylaminobenzoicacidethylester (DMABEE) were detected and quantified using gas chromatography–mass spectrometry (GC–MS). The amounts of the detected analytes from 100 mg polymerized composites ranged between the following values: TEGDMA: 0–0.5 mg (water), 0–1.6 mg (methanol); BHT: 0–0.03 μg (water), 0–0.11 mg (methanol); and DMABEE: 0–0.11 mg (water), 0–1.4 mg (methanol). We conclude from the results that the elution rates into methanol and water differ significantly. Furthermore, it is concluded that all the determined amounts eluting from the composites are far below toxic-relevant concentrations.

Keywords: Triethyleneglycoledimethacrylate (TEGDMA); 2,6-Di-t-butyl-4-methylphenol (BHT); 4-N,N-dimethylaminobenzoic acid ethylester (DMABEE); Elution; Quantification; Analysis

Sections

Personal tools

Archives of Toxicology (v.83, #12)

Sections

Personal tools

Local resources

Archives of Toxicology (v.83, #12)