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Archives of Toxicology (v.69, #4)

Evaluation of respiratory effects of thermal decomposition products following single and repeated exposures of guinea pigs by Katherine Detwiler-Okabayashi; Michelle Schaper (pp. 215-227).

Groups of guinea pigs were exposed to the thermal decomposition products (TDP) released from acrylonitrile butadiene styrene (ABS), polypropylene-polyethylene copolymer (CP), polypropylene homopolymer (HP), or plasticized polyvinyl chloride (PVC). In single 50-min exposures to the TDP, guinea pigs exhibited sensory irritation, coughing, and airways constriction. Significant decreases in respiratory frequency (f) occurred during TDP exposure which were magnified during CO₂ challenge conducted immediately post-exposure. For each resin, it was possible to demonstrate a linear relationship between the logarithm of heated mass and the percent decrease in f during CO₂ challenge. From these relationships, the mass of each resin producing a 50% decrease in f during CO₂ challenge (RD₅₀ mass) was obtained. RD₅₀ masses of 2744, 25.2, 16.0, and 6.7 g were obtained for ABS, CP, HP, and PVC, respectively. Thus, the relative potency of their TDP was PVC>CP ≈HP≫ ABS. Using the RD₅₀ mass of each resin, guinea pigs were exposed to TDP for 50 min/day on 5 consecutive days. These repeated exposures also resulted in sensory irritation, coughing, and airways constriction. However, deaths occurred during exposures, and there was evidence of cumulative respiratory effects, and slower recoveries among survivors. Data obtained in guinea pigs were compared to a previous study with mice exposed to the TDP of the same four resins (Schaper et al. 1994). On the basis of heated mass, mice were 20–500 times more sensitive to the acute respiratory effects of TDP than guinea pigs. Thus, the exposure limits of 0.63, 0.11, 0.08, and 0.35 mg/m³ proposed by Schaper et al. (1994) on the basis of particulates released from ABS, CP, HP and PVC should prevent not only irritation, but also possible coughing, and airways constriction in workers.

Keywords: Respiratory effects; Guinea pigs; Thermal decomposition products; Acrylonitrile butadiene styrene; Polypropylene-polyethylene copolymer; Polypropylene homopolymer; Plasticized polyvinyl chloride

Selenium concentrations in brain after exposure to methylmercury: relations between the inorganic mercury fraction and selenium by Lars Björkman; Karle Mottet; Magnus Nylander; Marie Vahter; Birger Lin; Lars Friberg (pp. 228-234).

Three groups of female monkeys (Macaca fascicularies) were exposed to methylmercury (MeHg, p.o. 50 μg Hg/kg body wt per day) for 6, 12, or 18 months. One group was exposed to MeHg for 12 months and kept unexposed for 6 months before sacrifice. Another group of three monkeys was exposed to HgCl₂ i.v. for 3 months. Total and inorganic mercury concentrations in occipital pole and thalamus were determined by cold vapor atomic absorption spectroscopy. Selenium concentrations were analyzed by hydride generation atomic absorption spectroscopy. The results indicated an association between concentrations of inorganic mercury and selenium in both occipital pole and thalamus in the MeHg-exposed animals. A linear regression model using concentrations of inorganic mercury (nmol/g wet wt) as independent variable, and selenium concentrations (nmol/g wet wt) as the dependent variable showed significant correlations between the variables in both occipital pole and thalamus (r=0.85 and r=0.91, P<0.0001). The intercept of the regression line was slightly lower (about 2 nmol Se/g wet wt) than the selenium concentrations found in control monkeys (about 3 nmol Se/g wet wt). There was a tendency to a “hockey stick”-shaped relationship between concentrations of selenium and inorganic mercury in the thalamus of monkeys with ongoing exposure to MeHg. An important role for selenium in the retention of mercury in brain is indicated.

Keywords: Brain; Selenium; Inorganic mercury Methylmercury; Monkeys

Lactational exposure to methylmercury in the hamster by Kerstin Nordenhäll; Lennart Dock; Marie Vahter (pp. 235-241).

Syrian Golden hamster dams were administered ²⁰³Hg-labelled methyl mercury (MeHg; 1.6 μmol/kg) 1 day after parturition and milk was collected twice during the 1st week. The excretion of ²⁰³Hg in milk and the uptake, retention and tissue distribution of ²⁰³Hg in the pups was studied using gamma counting. The fraction of inorganic Hg in milk and in the kidneys of the pups was determined following separation of inorganic Hg and MeHg by ion exchange chromatography. The concentration of ²⁰³Hg in milk on the 1st day after MeHg administration was 0.12 nmol/g. ²⁰³Hg was mainly (80–90%) excreted as MeHg during the first 6 days of lactation. The whole body and tissue concentration of ²⁰³Hg in the pups increased for 10–15 days and decreased thereafter. The content of ²⁰³Hg in the pelt and the fraction of inorganic Hg in the kidney increased throughout the study period (4 weeks). The excretion of MeHg in milk corresponded to at least 5% of the dose administered to the dam. Our study demonstrates that breast milk may be a significant source of MeHg exposure during the critical neonatal period.

Keywords: Methylmercury; Hamster; Breast milk; Mercury speciation; Mercury distribution

Differential localisation of UDP-glucuronosyltransferase in kidney during human embryonic and fetal development by R. Hume; M. W. H. Coughtrie; B. Burchell (pp. 242-247).

The aim of our study was to localise UDP-glucuronosyltransferase (UDPGT) in the developing mesonephric and metanephric kidneys of the human embryo and fetus, using immunohistochemical methods and an antibody preparation with broad specificity to the human isoforms. In embryonic and early fetal development of the metanephric kidney, UDPGT is located primarily in derivatives of the ureteric bud such as the ureter, pelvis, calyces and collecting ducts. This early predominance of UDPGT to ureteric bud derivatives declines by mid-fetal life: a) as nephrons evolve and develop they become increasingly UDPGT immunoreactive such that in mature metanephric kidney, the proximal tubules are highly UDPGT reactive, with other elements of the nephron also immunopositive (albeit at lower reactivities) and b) with the formation of an immunonegative transitional epithelium in ureter, pelvis and calyces, the reactivity retained in collecting ducts is only a small proportion of the total. The distribution of UDPGT immunoreactivity is relatively uniform in proximal tubular cells throughout development. This is in contrast to collecting ducts where, in fetal life, this reactivity is displaced to apices and bases by intracellular glycogen deposits. Parietal cells of Bowman’s capsule are immunoreactive, but glomeruli are negative. In mesonephric kidney, as early as 32 days post-ovulation, tubules and the mesonephric duct are UDPGT immunoreactive and mesonephric immunopositivity overlaps with that in the developing metanephric kidney.

Keywords: Immunohistochemistry; UDP-glucuronosyltransferase; Human; Development; Kidney

Tubular effects of acetaminophen in the isolated perfused rat kidney by Laura Trumper; Liliana A. Monasterolo; Elena Ochoa; M. Monica Elias (pp. 248-252).

The effects of different acetaminophen (APAP) concentrations (1,5 or 10 mM) on renal function were investigated in the isolated perfused rat kidney (IPK). APAP was added to the perfusion media as a single dose after a equilibration time and control periods. Changes in fractional excretion of sodium (FE_Na), water $$left( {FE_{H_2 O} } ight)$$ , glucose (FE_glu) and in glomerular filtration rate (GFR) were measured. The lower concentration used only modified the $$FE_{H_2 O} $$ . APAP 10 mM induced an increment in $$FE_{H_2 O} $$ (72% higher than control preparation), FE_Na (79% higher than control preparation) and an elevation in glucose excretion (55% higher than control preparation), associated with a decrease in GFR (23% lower than control preparation). The influence of PGE₂ on the effects of APAP was also investigated. PGE₂ prevented the APAP-induced decrease in GFR and in glucose reabsorption, but did not change the pattern of sodium and water handling. The effects of another vasodilator, verapamil, on APAP-induced renal effects were also tested. Verapamil prevented the glomerular but not the tubular effects of APAP. Urinary APAP excretion data showed a similar availability of APAP to the tubular cells in all the groups. Our data suggest that APAP exerts a direct action in the IPK, affecting hemodynamic and tubular functions, and that the latter are not a consequence of hemodynamic alterations.

Keywords: Acetaminophen; Nephrotoxicity; Isolated perfused kidney

Expression of clusterin (testosterone-repressed prostate message-2) mRNA during growth and regeneration of rat liver by W. Bursch; T. Gleeson; L. Kleine; M. Tenniswood (pp. 253-258).

Clusterin has been used as a marker for apoptosis (often denoted “active” “or programmed” cell death) in the prostate, mammary gland and other solid organs. The protein is thought to be involved in membrane remodelling during separation of apoptotic cells from their vital neigh-bours and fragmentation into apoptotic bodies. In the present study, we have looked at the expression of clusterin during the growth and regression of rat liver induced by short term administration of the hepatomitogen, cyproterone acetate. The steady state level of clusterin mRNA, as measured by Northern and slot blot analysis, is low in control hepatocytes. Following administration of cyproterone acetate, the clusterin mRNA level is increased during both liver growth and regression. In situ hybridization reveals that clusterin is expressed in all hepatocytes, indicating that it is not confined to cell death by apoptosis. These results suggest that the gene product may be involved in maintaining membrane integrity, which is necessary during both mitosis and apoptosis. To determine whether clusterin mRNA is induced by membrane remodelling independent of either mitosis or apoptosis, we examined the expression of clusterin mRNA in the liver after a necrogenic dose of carbon tetrachloride. During the first 24–48 h of this time period, necrosis is the predominant form of cell death and liver regeneration starts after approximately 24 h. Elevated levels of clusterin mRNA are found as early as 12 h after carbon tetrachloride administration and persist for at least 72 h. Clusterin expression in tissues such as the prostate and mammary gland appears to be confined to the apoptotic pathway; however, our results suggest that in hepatocytes, the expression of the gene is induced in processes other than apoptosis, including mitosis and necrosis. These processes involve substantial membrane remodelling, suggesting that clusterin expression may be induced by perturbations in the normal membrane structure.

Keywords: Clusterin; Liver; Apoptosis; Mitosis; Necrosis; Cyproterone acetate; Carbon tetrachloride

Effect of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin on growth factor expression in the human breast cancer cell line MCF-7 by Christoph Vogel; Josef Abel (pp. 259-265).

The aim of this study was to examine whether changes in growth factor or cytokine expression could be responsible for the growth inhibitory effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the human breast cancer MCF-7 cell line. Treatment of MCF-7 cells with 10 nM TCDD for 7 days reduced the cell growth to 60% of control; this effect was partly abolished by cotreatment of the cells with 100 nM 17β-estradiol (E₂). The inhibition of cell growth by TCDD was accompanied by an enhanced secretion of transforming growth factor-β (TGF-β) and the TGF-β content in cell culture supernatants was 2-fold higher than in controls. Using reverse transcription polymerase chain reaction (RT-PCR), the effect of TCDD on the expression of TGF-β isoforms, transforming growht factor-α (TGF-α), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was investigated. It was demonstrated that incubation with 1, 10 and 100 nM TCDD for 24 h increased mRNA levels of TGF-α, TNF-α and IL-1β. The strongest effect was found on IL-1β, the mRNA level of which was dose-dependently increased. TCDD had a minor effect on TGF-α and TNF-α mRNA. The mRNA levels were significantly increased after treatment with 10 and 100 nM TCDD. The mRNA expression of $$TGF - eta _1 $$ and $$TGF - eta _2 $$ was unchanged, whereas the $$TGF - eta _3 $$ mRNA level was enhanced 2 to 3-fold after TCDD treatment. From the results, we suggest that TCDD-induced growth inhibition in MCF-7 cells is related to the growth inhibitory action of a set of growth factors and cytokines which have a contextual action on MCF-7 cell proliferation.

Keywords: 2,3,7,8-TCDD; Cell growth; Transforming growth factor; Tumor necrosis factor; Interleukin-1; MCF-7 cells

Accumulation of 3-(phenylamino)alanine, a constituent in l-tryptophan products implicated in eosinophilia-myalgia syndrome, in blood and organs of the Lewis rats by Junko Adachi; Maria Gomez; Craig C. Smith; Esther M. Sternberg (pp. 266-270).

3-(Phenylamino)alanine (PAA), a newly discovered impurity in case-associated l-tryptophan tablets, has been investigated as a possible contributing factor in the etiology of eosinophilia-myalgia syndrome (EMS). We have studied distribution and elimination of PAA in rats which were administered a single 5 mg/kg dose of PAA by gastric gavage. PAA concentrations in blood, brain, kidney and liver were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. The concentration of PAA in each tissue reached a maximum at 5 h, and then gradually declined. A high level of PAA still remained at 24 h, indicating gradual elimination. The concentration of PAA in brain at 5 h was 2139 ng/g tissue, demonstrating passage through the blood-brain barrier. Consecutive administration of PAA (5 mg/kg) for 4 days resulted in approximately double the concentration in all tissues. Chronic treatment using PAA incorporated into food pellets for 6 weeks resulted in similar accumulations in each tissue, and following 12 days on a PAA free diet, levels of this drug were still detectable in all tissues.

Keywords: 3-(Phenylamino)alanine; l-Tryptophan; Eosinophilia-myalgia syndrome; Lewis rat

Four generation reproductive toxicity study with 2,3,7,8-tetrachlorodibenzo-P-dioxin (TCDD) in rats by E. Koch; E. Thiel; E. Chahoud; D. Neubert (pp. 271-279).

A multigeneration study on the reproductive toxicity of TCDD in rats was conducted. In this paper, the results of extensive pharmacokinetic evaluations are presented. The time course of tissue concentrations within the framework of a multigeneration study was investigated, using radioactive labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a substance with a long elimination half-life. So far, long term exposure to TCDD has generally been conducted by administering the same daily doses via the feed. Since the half-life of TCDD in rats is several weeks, the concentration of the test substance can be predicted to change continuously during such a study. Therefore we intended to expose the animals to a constant tissue concentration by using a loading dose/maintenance dose approach. To achieve this, the animals were treated with initial loading doses of 50, 120 or 250 ng TCDD/kg body wt. Based on the elimination half-life of 3 weeks and a planned dosing interval of 7 days, the weekly maintenance doses were calculated to be 20% of the loading dose. During the postnatal phase of rapid growth, this dosing schedule was insufficient to keep the tissue concentration of TCDD constant. It was necessary to administer a second loading dose and to increase the weekly maintenance dose to 40% of the loading dose. While it was possible to control the tissue concentrations in the F₀ generation, a considerably larger variation was observed during the different developmental stages of the F₁ generation. The fluctuations could be reduced by using a complex dosing schedule, but even with that it was impossible to achieve completely steady levels in liver and adipose tissue. This was mainly due to the fact that levels in liver and adipose tissue did not change together. In the case of a lipophilic substance with a long elimination half-life, attempts at a risk assessment on the basis of a multigeneration test cannot rest on the assumption of defined tissue levels during the study while pharmacokinetic variables are difficult to control in such a study.

Keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin TCDD; Toxicokinetics; Tissue distribution

Sister chromatid exchange frequency in cultured isolated porcine urinary bladder epithelial cells (PUBEC) treated with ochratoxin A and alpha by W. Föllmann; I. E. Hillebrand; E. E. Creppy; H. M. Bolt (pp. 280-286).

The mycotoxin ochratoxin A (OTA) and its metabolite ochratoxin alpha (OT-alpha) were investigated, to examine their potency to induce sister chromatid exchages (SCE) in cultured poricine urinary baldder epithedial cells (PUBEC) (primary cluture). Serum-free cultured PUBEC were incubated for 5 h with either OTA or OT-alpha, respectively, and subsequently cutured in the presence of 5-bromo-2-deoxyuridine (BrdU). After two cell cycles, mitosis was inhibited by the colchicine derivative Colcemid, cells were fixed and chromosomes were prepared for SCE analysis. For OTA, a dose-dependent increase in SCE frequency was measured in concentrations between 100 pM and 100 nM OTA. At 100nM OTA, SCE frequency increased by about 41%, compared to the base SCE level (7.27 SCEs per chromosome set, solvent control). Higher concentrations of OTA were cytotoxic. The metabolite OT-alpha also increased SCE frequency, but at higher concentrations. At a concentration of 10μM OT-alpha, an increase of about 55% was detected. OT-alpha showed no cytotoxic effect. There results indicate that OTA is genotoxic in this in vitro system, which represents the urinary bladder epithelium, a target organ of OTA in vivo. It could also be shown that OT-alpha, which is said to be non-toxic, is genotoxic in this assay at higher concentrations.

Keywords: Mycotoxin; Ochratoxin A; Genotoxic effects; PUBEC; SCE frequency

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Archives of Toxicology (v.69, #4)