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Archives of Toxicology (v.73, #3)

Studies on the dermal and systemic bioavailability of polycyclic aromatic compounds in high viscosity oil products by David Potter; Ewan D. Booth; Henk C. A. Brandt; Robert W. Loose; Robert A. J. Priston; Alan S. Wright; William P. Watson (pp. 129-140).

The assessment of skin penetration by viscous oil products is an important element in the risk assessment of these materials where skin contact is likely. Systemic bioavailability (body uptake) is viewed as a good indicator of skin penetration following cutaneous exposures. The results of this study provide quantitative information on the influence of viscosity on the bioavailability of a specific polycyclic aromatic compound (benzo(a)pyrene) in base oils, residual aromatic extracts and bitumens following skin exposures to mice. The materials studied were a base mineral oil (viscosity 32 cSt at 35 °C), a 1:1 blend of the mineral base oil and a residual aromatic extract (198 cSt), several residual aromatic extracts (ca. 5000 cSt, 35 °C) and a range of bitumens (0.65–69 × 10⁶ cSt, 35 °C). These were each spiked with 0.1% radiolabelled benzo(a)pyrene, as a representative carcinogenic polycyclic aromatic compound, then used for cutaneous exposures to mice. The results indicate that as viscosity increased in the range ca. 30 to 5000 cSt (base oil to residual aromatic extract) the uptake of the radiolabelled benzo(a)pyrene into blood was reduced by ca. fivefold. Further increases in viscosity from ca. 5000 to 69 × 10⁶ cSt (i.e. residual aromatic extract to bitumen) resulted in a further but smaller (ca. twofold) reduction in uptake. The relationship between the amounts of free benzo(a)pyrene measured in blood and viscosity showed the same trend. This trend was also mirrored by the degree of binding of benzo(a)pyrene metabolites to DNA in skin. The findings in mouse skin in vivo indicate that viscosity can significantly affect skin penetration and systemic bioavailability of polycyclic aromatic compound components of oil products. Results obtained with viable human skin in vitro also showed that the bioavailability of benzo(a)pyrene was reduced by the viscosity of the oil product matrix. It is thus necessary to take account of physical properties such as viscosity in the overall risk assessment of viscous oil products, particularly in the case of very viscous materials such as bitumens. The significantly reduced bioavailability of hazardous compounds from undiluted materials is thus an important factor to consider when assessing the risks from dermal exposures.

Keywords: Key words Bitumen; Mineral oil; Benzo(a)pyrene; Bioavailability; Skin

Effects of N-nitrosodimethylamine (NDMA) on the oxidative status of rat liver by M. Taniguchi; A. Yasutake; K. Takedomi; K. Inoue (pp. 141-146).

To investigate oxidative effects of N-nitrosodimethylamine (NDMA) on the liver, rats were challenged by the reagent with a dose range of 10 to 40 mg/kg. With lower dose levels, protective responses were prominent, such as elevation of the hepatic glutathione and metallothionein (MT) levels. Increased activities were also evident of γ-glutamylcysteine synthetase, glucose-6-phosphate dehydrogenase (G6PD), and malic enzyme. In the high dose range, however, toxic responses, such as increases in lipid peroxide levels in liver and serum, and glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), and ketone bodies in serum became marked. Some of the protective responses became less marked at the highest dose. Catalase and glutathione peroxidase activities in the liver were also inhibited by NDMA treatment. On the other hand, when NDMA was injected as a series of doses (10 mg/kg on four separate occasions), the effects were less marked, and the hepatic levels of MT and lipid peroxide remained unchanged even after the 4th injection. Only the increase in G6PD activity was more marked after four times repeated injection than after a single injection. These results suggest that oxidative and hepatotoxic effects of NDMA are more moderate when given in repeated doses than in a single dose. In contrast to the liver, elevation of MT levels was the only detectable change in the kidney.

Keywords: Key words Nitrosodimethylamine; Glutathione; Metallothionein; Oxidative stress; Liver

Imipramine- and mianserin-induced acute cell injury in primary cultured rat hepatocytes: implication of different cytochrome P450 enzymes by Yasuhiro Masubuchi; Maki Konishi; Toshiharu Horie (pp. 147-151).

The antidepressants, imipramine and mianserin, have been reported to cause liver damage. We investigated a role of cytochrome P450 (CYP)-mediated formation of a reactive metabolite in antidepressant-induced acute cell injury using hepatocytes isolated from male and female Wistar rats, and male Dark Agouti rats, which have different relative abundance of CYP enzymes. Culture of the hepatocytes with imipramine and mianserin caused a marked decrease in glutathione followed by protein thiol, which preceded lactate dehydrogenase leakage. The decreases in glutathione and protein thiol contents by imipramine were significantly slower in hepatocytes from male Dark Agouti rats than those from male Wistar rats, whereas no significant sex difference in Wistar rats was observed. The decrease in thiol by mianserin was significantly slower in hepatocytes from female Wistar than those from male Wistar rats, whereas no significant differences were found between Wistar and Dark Agouti males. Results consistent with alteration of the thiols were obtained for lactate dehydrogenase leakage induced by imipramine and mianserin. These findings indicated that CYP-mediated metabolic activation was involved in acute cell injury induced by the antidepressants; namely a CYP2D enzyme(s), which is deficient in Dark Agouti rats, and a male specific CYP enzyme(s) were suggested to be responsible for the cytotoxicity of imipramine and mianserin, respectively.

Keywords: Key words Imipramine; Mianserin; Cytochrome P450; Hepatotoxicity; Hepatocytes

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-mediated membrane translocation of c-Src protein kinase in liver WB-F344 cells by Christoph Köhle; Harald Gschaidmeier; Dennis Lauth; Simon Topell; Heike Zitzer; Karl Walter Bock (pp. 152-158).

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant and the most potent agonist of the aryl hydrocarbon receptor (AhR). Persistent activation of the AhR has been shown to be responsible for most TCDD-mediated toxic responses, including liver tumour promotion. However, the mechanisms responsible for these complex toxic reactions are still unknown. TCDD (1 nM) has previously been shown to reduce DNA synthesis of primary hepatocyte cultures and cell contact inhibition of confluent WB-F344 cells. The latter model was used to study early effects of TCDD on protein tyrosine kinase c-Src in confluent WB-F344 cells. It was found that TCDD decreased cytosolic c-Src (protein and tyrosine kinase activity) after 20–60 min, and increased c-Src in the membrane fraction. Membrane translocation of c-Src occurred in the presence of 100 μM cycloheximide and was observed after treatment with 1 nM TCDD or 50 nM 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin. Under these conditions epidermal growth factor (EGF) receptor tyrosine phosphorylation was also studied. As expected, its phosphorylation was low in confluent cells but was significantly enhanced by TCDD treatment. Pretreatment of WB-F344 cells for 1 h with 1 μM geldanamycin, which disrupts cytosolic heat shock protein Hsp90 complexes with AhR and Src, abolished TCDD-mediated Src translocation and TCDD-mediated reduction of cell contact inhibition. The WB-F344 cell model appears to be very useful to study TCDD effects on protein tyrosine kinases and of signaling pathways responsible for modulation of the cell cycle by TCDD.

Keywords: Key words Aryl hydrocarbon receptor; Dioxins; c-Src protein kinase; EGF receptor; WB-F344 cells

T cell-dependent immune reactions to reactive benzene metabolites in mice by Susanne Ewens; Marty Wulferink; Carsten Goebel; Ernst Gleichmann (pp. 159-167).

Using the popliteal lymph node (PLN) assay in mice, we studied the sensitizing potential of benzene and its metabolites. Whereas benzene and phenol failed to induce a PLN reaction, catechol and hydroquinone induced a moderate, and p-benzoquinone a vigorous response. Following a single injection of the reactive metabolite p-benzoquinone (100 nmol/mouse), cellularity in the draining PLN was increased >15-fold, and reverted back to normal only after ∼100 days. Although the PLN response was T cell-dependent, flow cytometric analysis revealed that the increased cellularity in the PLN after a single injection of p-benzoquinone was mainly due to an increase in B cells. Mice primed to p-benzoquinone and challenged with a small dose of p-benzoquinone (0.1 nmol/mouse) mounted a secondary PLN reaction, indicating hapten specificity of the reaction; this was confirmed by results obtained in the adoptive transfer PLN assay. An unexpected finding was the secondary PLN response to benzene (1 nmol/mouse) observed in mice primed to p-benzoquinone. This finding suggests that some of the benzene (at least 10%) was locally converted into p-benzoquinone, which then elicited the secondary response observed. In conclusion, the reactive intermediate metabolites hydroquinone and p-benzoquinone can act as haptens and sensitize; their precursors, benzene and phenol, may be considered as prohaptens.

Keywords: Key words Benzene; Benzoquinone; Hydroquinone; T-cell; Immunotoxicity

Immunotoxicity of the anticancer drug CI-994 in rats: effects on lymphoid tissue by Michael J. Graziano; Anthony J. Galati; Kathleen M. Walsh (pp. 168-174).

CI-994 (acetyldinaline) is an investigative oral anticancer drug currently in clinical trials. To characterize the effects of CI-994 on lymphoid tissue, male rats were administered single oral doses at 0 (vehicle control), 10, 23, and 45 mg/kg and killed up to 7 days after dosing for evaluation of white blood cell differentials, bone marrow differentials, lymphoid tissue weights, and selected histopathology of lymphoid tissue. Statistically significant dose-related reductions in blood lymphocytes (CD-3⁺, CD-4⁺, CD-8⁺, CD-20⁺), monocytes, neutrophils, and bone marrow lymphoid cells were observed in all drug-treated groups on days 1 and/or 3. Statistically significant reductions in bone marrow myeloid cells were also observed on days 1 and 3 at 23 and 45 mg/kg. Complete or partial reversal of most parameters was evident on day 7. Spleen and/or thymus weights were significantly decreased in the groups administered 23 and 45 mg/kg on days 1, 3, and/or 7. Minor reductions in lymphoid organ weights were noted at 10 mg/kg. Minimal to moderate lymphoid depletion of the spleen and thymus was noted on day 3 in animals dosed at 23 mg/kg. In vitro, CI-994 inhibited mitogen-stimulated blood lymphocyte proliferation with a 50% inhibitory concentration (IC₅₀) value of 3 μM. The results demonstrate that CI-994 can effect lymphoid tissue in rats within 1 day of a single oral dose, that effects are generally reversible within 7 days, and that inhibition of lymphocyte proliferation is a sensitive indicator of CI-994 immunotoxicity in vitro.

Keywords: Key words CI-994; Acetyldinaline; Immunotoxicity; Lymphocyte proliferation; Rats

Suppression of uterine decidualization as a cause of implantation failure induced by triphenyltin chloride in rats by Makoto Ema; Emiko Miyawaki; Kunio Kawashima (pp. 175-179).

In our previous study, triphenyltin chloride (TPTCl) was found to induce implantation failure, as preimplantation embryonic loss, in rats. In this study, the effects of TPTCl on the uterine function, as a cause of implantation failure, were determined using pseudopregnant rats. Female rats were given TPTCl by gastric intubation at 3.1, 4.7, and 6.3 mg/kg on pseudopregnant day (PPD) 0 to PPD 3 and the decidual cell response was induced on PPD 4. The uterine weight on PPD 9 served as an index of uterine decidualization. A significant decrease in the uterine weight, which indicates suppression of the uterine decidualization, was detected at 4.7 and 6.3 mg/kg. In our previous study, these doses induced a significant increase in implantation failure in female rats given TPTCl on gestational day (GD) 0 to 3. The ovarian weight and number of corpora lutea in the TPTCl-treated groups were comparable to that of the controls. A significant decrease in serum progesterone levels after administration of TPTCl was found at 4.7 and 6.3 mg/kg. These findings suggest that implantation failure due to TPTCl may be mediated via the suppression of uterine decidualization and correlated with the reduction in serum progesterone levels.

Keywords: Key words Triphenyltin; Implantation failure; Decidual cell response; Uterine function; Pseudopregnancy

Development of a carcinogenic potency index for dermal exposure to viscous oil products by Henk C. A. Brandt; Ewan D. Booth; Paul C. de Groot; William P. Watson (pp. 180-188).

Polycyclic aromatic compounds (PACs) present in oil streams and formulated products are important determinants of possible carcinogenicity. Following dermal exposures the transport of the PACs from oil (the carrier) into the skin is a factor that may affect macromolecular (DNA) adduct formation and thus determine carcinogenicity. We have developed a mathematical model, which describes the flux into the skin for a representative carcinogenic PAC, benzo(a)pyrene. The model is based on measurements of the amount of benzo(a)pyrene bound to skin DNA or blood observed in mouse skin painting studies. The degree of adduct formation from a particular oil product, which we term the Bioavailability Index (BI), was shown to be a function of both the viscosity of the oil product, which affected the transport of the PAC through the carrier, and the aromaticity, which affected the partition of PAC between the carrier and the skin. Literature data were analysed from mouse skin painting studies with mineral oils of known carcinogenicity. A linear relationship was shown between the amount of DNA adduct formation, expressed as alkylation frequency, and the arithmetic product of the total (3–6) ring PAC content and the BI, which we have termed the Carcinogenic Potency Index (CPI). Comparison of literature data on DNA alkylation frequencies for oil products and their carcinogenicity indicated that oils giving rise to an alkylation frequency below a certain threshold (ca. 1 adduct in 10⁸ nucleotides) are non-carcinogenic to mouse skin. This threshold level can be translated into a value for the CPI, below which the genotoxic carcinogenic risk arising from skin contact with the oil product is considered to be negligible. The CPI for bitumens is well below this value, being both due to the low BI from bitumen, but more so, due to their low PAC content. For some bitumens diluted with solvents, i.e. cutback-bitumens, the CPI may exceed this value, indicating a possible carcinogenic risk for some of the cutback-bitumens. The main determining factor is the PAC content which is principally determined by the nature of the diluent used.

Keywords: Key words Bitumen; Mineral oil; Benzo(a)pyrene; Bioavailability; Carcinogenic potency

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Archives of Toxicology (v.73, #3)