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Archives of Toxicology (v.78, #5)
Acute inhalation studies with irritant aerosols: technical issues and relevance for risk characterization by Jürgen Pauluhn (pp. 243-251).
Current testing conventions for inhalation toxicity studies require that solid and non-volatile liquid compounds are converted to respirable aerosol, which is often achieved by laboratory-specific technical methodologies. So far, internationally harmonized approaches are lacking that would allow comparison of results from inhalation studies with ‘contrived’ test aerosols taking into account the actual particle size of the product as it might be encountered in normal handling and use. The focus of this paper is to consider aerosols of irritant substances eliciting their mode of action on sites of initial deposition within the respiratory tract of rats. Assessment is based on conventional endpoints, such as mortality (LC50), and sublethal endpoints that include an analysis for the concentration–effect relationship of protein in bronchoalveolar lavage fluid (BAL-protein) as a sensitive, early marker of lung edema. This retrospective analysis also addresses whether common denominators can be found for different aerosol sizes of direct and indirect irritants, such as monomeric and polymeric diphenylmethane-4,4′-diisocyanate (mMDI and pMDI), naphthylene diisocyanate (NDI), dicyclohexylmethane-4,4′-diisocyanate (HMDI), 2,4-triisopropyl-benzene-diisocyanate (TRIDI) and substances (e.g., chlorofluoroalkyl side-chain fungicides) known to decompose to irritant intermediates in the lining fluids of the airways. Collectively, this analysis shows that for irritant aerosols both the concentration and the particle size are equally important for the outcome of the test, independent of whether the endpoint chosen is lethality or BAL protein. The scientific value of 1-h exposures to high aerosol concentrations, as required by some regulations, could be challenged because high concentrations and high respirability of aerosol appear to be mutually exclusive, as shown for mMDI and NDI (LC50 >2000 mg/m3). Thus, for a meaningful risk characterization, test results from inhalation studies with ‘contrived properties’ due to the specific techniques employed need to be compared with the real properties of substances as marketed, handled and used.
Keywords: Aerosols; Respirability; Inhalability; Classification and labeling; Inhalation testing; Lung irritants; Pesticide dusts; Lung edema; MDI; NDI; HMDI; TRIDI; Diisocyanate aerosols
Developmental toxicity of polychlorinated biphenyls (PCBs): a systematic review of experimental data by Beate Ulbrich; Ralf Stahlmann (pp. 252-268).
Experimental reproductive and developmental toxicity studies with polychlorinated biphenyls (PCBs) are reviewed in brief to determine their relevance for current environmental exposure of humans during the prenatal and postnatal developmental periods. Additional material is published in electronic form only, which contains graphic overviews on individual PCBs and various mixtures that are linked with the relevant citations. In this comprehensive article we focus on interactions of PCBs with biological substrates that could mediate adverse effects observed in experimental animals and in children, and the shortcomings of many of the animal studies available. A main point of criticism involves the relative lack of animal data on several of those persistent congeners, either as individual compounds or as environmentally relevant mixtures, which are currently used as a measure of human exposure. Experimental studies in animals are frequently conducted with commercial PCB mixtures, a test design that does not reflect the exposure situation in humans. Important improvements of animal experiments could be achieved by more complete reporting of litter data (pre- and post-natal losses, toxic signs in the dam and the offspring, birth weights and postnatal growth data), the inclusion of endpoints that have been found previously to be affected by PCBs, and measurements of internal exposure data.
Keywords: Polychlorinated biphenyls; Reproductive toxicity; Developmental toxicity; Human risk assessment; Review
A 13-week oral toxicity study of senna in the rat with an 8-week recovery period by U. Mengs; J. Mitchell; S. McPherson; R. Gregson; J. Tigner (pp. 269-275).
Senna was administered by gavage to Sprague Dawley rats once daily at dose levels of 0, 100, 300, 750 or 1500 mg/kg for up to 13 consecutive weeks followed by an 8-week recovery period for selected animals. Dose- and treatment-related clinical signs included abnormal feces, which were seen to varying degrees from animals at 300 mg/kg per day and more. Animals receiving 750 or 1500 mg/kg per day had significantly reduced body weight gain (males only) and, related to the laxative properties of senna, increased water consumption and notable changes in electrolytes in both serum and urine. At both the terminal and recovery phase necropsy, an increase in absolute and relative kidney weights was seen for male and female animals receiving 750 and/or 1500 mg/kg per day. A dark discoloration of the kidneys was observed at necropsy along with histopathological changes in the kidneys (slight to moderate tubular basophilia and pigment deposits) at 300 mg/kg and above. However, there were no indications in laboratory parameters of any renal dysfunction. In addition, for all treated groups, minimal to slight hyperplasia was recorded in the forestomach and large intestine. Following 8 weeks of recovery, with the exception of the brown pigment in the kidneys, there were no histopathological abnormalities. Thus, the biochemical and morphological changes seen following 13 weeks of treatment of senna significantly reversed following 8 weeks of recovery.
Keywords: Senna; Anthranoids; Toxicology; Subchronic toxicity; Rat
Evaluation of the effects of aluminium, ethanol and their combination on rat brain synaptosomal integral proteins in vitro and after 90-day oral exposure by T. Kohila; E. Parkkonen; H. Tähti (pp. 276-282).
The effects of aluminium lactate (Al-lactate) on the rat cerebral synaptosome integral proteins adenosinetriphosphatase (ATPase) and acetylcholinesterase (AChE) were studied in vitro and in vivo. Coexposure with ethanol (EtOH) was studied in both situations. Isolation of synaptosomes was carried out using isoosmotic Percoll gradients. In in vitro experiments, the synaptosomes were exposed to different concentrations of Al-lactate in the incubation mixture. Al-lactate caused decreases in total ATPase and AChE activities concentration dependently. The decrease in ATP activity started at 0.2 mM concentration, and concentration for the 50% decrease of the enzyme activity (EC50 ) was 1.1 mM. The decrease in AChE activity started at 5–10 mM concentration, and the EC50 value was 15.8 mM. Coexposure with ethanol (2 mM) increased the EC50 values similarly in both cases. After 90-day oral exposure of rats to Al-lactate (91.8 mg/kg/day), the serum aluminium level was 0.9–1.3 μM/l. Coexposure with EtOH (3.0 g/kg/day) did not significantly increase the blood Al (0.7–2.2 μM/l). Aluminium exposure caused a decrease in the blood EtOH concentration (0.6 mM/l) compared with blood EtOH (12.3 mM/l) in the rats exposed to ethanol only. In the rats studied 2 weeks after the Al exposure, the activities of ATPase and AChE were significantly lower than in the rats studied immediately after the exposure. Correspondingly, a significant decrease in AChE activity was found in Al- and EtOH-exposed rats, but in the control rats there were no differences between the study groups. Immediately after the 90-day dosing, the exposed rats did not differ significantly from the control rats. Based on the in vitro results, the neural membrane integral proteins ATPase and AChE may be considered as targets for the effects of aluminium and ethanol. Ninety-day in vivo exposure of rats to aluminium caused decrease in ATPase and AChE activities, detectable 2 weeks after the exposure.
Keywords: Aluminium; Ethanol; Synaptosomes; ATPase; AChE
Low iron diet retards 12-O-tetradecanoyl phorbol-13-acetate-mediated tumor promotion in murine skin by Gayatri Bhasin; Hina Kauser; Mohammad Athar (pp. 283-289).
Recently, we have shown that low iron state reduces benzoyl peroxide-mediated tumor promotion in murine skin. To further test the dependence of iron on skin tumor development, we assessed the effect of a low iron diet on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-mediated tumor promotion in murine skin. Female Swiss albino mice were fed on a low iron diet and initiated with a single dose of 7,12-dimethylbenz[a]anthracene (DMBA, 40 µg as150 µl per mouse) and promoted with TPA (2.5 µg as 200 µl per mouse, twice-weekly application for 20 weeks). The appearance of the first papilloma and the number of tumors (papillomas and carcinomas) per mouse were recorded weekly. We observed a decrease in tumor incidence (papillomas and carcinomas) and number of tumors per mouse in TPA-promoted mice fed on low iron diet (0.23 mg Fe/kg diet) compared to normal mice fed on balanced mouse chow (1.70 mg Fe/kg diet). The total iron consumption per day by mice being fed on balanced mouse chow was 340–400 µg Fe/kg body weight, and the total iron consumption per day by mice being fed on low iron diet was 45–55 µg Fe/kg body weight. The number of papillomas per mouse was 45% lower and the conversion of papillomas to carcinomas was about 20% lower in mice fed a low iron diet. The tumor size was also smaller in mice being fed on low iron diet. TPA treatment resulted in decreases in the activities of antioxidant enzymes and depletion in the level of epidermal reduced glutathione (GSH). Feeding mice on low iron diet along with TPA treatment resulted in ~50–75% recovery of the depleted levels of GSH and antioxidant enzymes. In addition, TPA-mediated induction of biological markers of tumor promotion, viz. ornithine decarboxylase activity and [3H]thymidine incorporation into cutaneous DNA, was about 60% lower in TPA-treated mice fed on low iron diet than in normal mice treated with TPA. Cutaneous iron levels were also lower in mice fed on low iron diet than in mice fed on normal diet. Histopathological sections of the skin portion adjoining tumors showed a lower degree of epidermal hyperplasia and lesser infiltration of inflammatory cells in the dermis, and absence of hyperkeratosis in mice fed on low iron diet. Thus, in this study we observe that the tumor promoting potential of TPA is reduced in mice fed on low iron diet, which is also accompanied by lesser inflammatory changes in the skin of tumor-bearing mice fed on low iron diet.
Keywords: Tumor promotion; Carcinogenesis; Low iron diet; Reactive oxygen species
Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on maternal immune response during pregnancy by Iris A. Camacho; Mitzi Nagarkatti; Prakash S. Nagarkatti (pp. 290-300).
Whether pregnancy-induced immunosuppression when combined with exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) could exacerbate immunotoxicity has not been previously investigated. The current study evaluated the immune status of C57BL/6 pregnant and virgin mice following exposure to TCDD. To this end, syngeneically pregnant or virgin female mice were injected intraperitoneally with 10 µg/kg TCDD. Pregnancy alone significantly decreased thymic cellularity and J11d expression as well as induced changes in T-cell subsets. TCDD treatment caused significant thymic atrophy in pregnant mice as early as 48 h after exposure, but this effect was apparent in virgin mice only after 72 h. TCDD treatment also caused more marked alterations in thymic T-cell subpopulations of pregnant mice when compared to the virgin mice, with a decrease in the percentage of double-positive T cells and an increase in the percentage of single-positive (sP CD4+ or sP CD8+) and double-negative T cells. Moreover, the proliferative responses of thymocytes, but not splenocytes, to mitogens were significantly altered in TCDD-treated pregnant mice when compared to the TCDD-treated virgin mice. Furthermore, no significant changes in the expression of CD4, CD8, B220 and NK1.1 markers were found in splenocytes from TCDD-treated virgin and pregnant mice. Immunization of mice with a superantigen caused a similar immunotoxic response in TCDD-treated pregnant and virgin mice with a decreased lymph node cellularity and lower percentages and cell numbers of Vβ3+ and Vβ11+ T cells. Together, the results of the current study demonstrate for the first time that pregnancy augments the sensitivity to TCDD-induced immunotoxicity in the thymus, but not in secondary lymphoid organs.
Keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD); Pregnancy; Immunosuppression; Immunotoxicity