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Archives of Toxicology (v.68, #7)

New scientific arguments for regulation of ethylene oxide residues in skin-care products by Johannes G. Filser; Paul E. Kreuzer; Helmut Greim; Hermann M. Bolt (pp. 401-405).

Ethylene oxide (EO) occurs as a contaminant of skin-care products because current commercial preparations of polyglycol ethers may contain ethylene oxide monomer residues, up to the order of 1 ppm. Using current regulatory worst-case assumptions, the presence of EO in skin-care products might lead to a maximal human daily external ethylene oxide dose of about 2.8 μg, and a consecutive maximal daily absorbed dose of 0.39 μg. Two methods of toxicokinetic analysis have been used to compare this possible EO load by use of skin-care products with the inevitable load of EO which is produced endogenously in the organism. On the basis of a previous assessment of the endogenous production of ethylene and ethylene oxide (Filser et al. 1992) it is inferred that the absorbed EO dose of 0.39 μg is about 1/30 of the unavoidable human endogenous load by endogenous EO. Alternatively, for a second calculation molecular dosimetry data have been used which were based on experimental quantification of the hydroxyethyl adduct of EO to the N-terminal valine of hemoglobin (HOEtVal) in rats. If the worst-case assumptions for human EO absorption from skin-care products are transferred to the rat species, the associated internal EO doses are about 1/110 of the internal EO doses which were calculated from the background HOEtVal concentrations observed in untreated animals. The divergence between both lines of calculation is mainly due to differences in HOEtVal background concentrations between man and rat. It is concluded that the additional internal body burden of EO associated with the use of current skin-care products, even under a series of worst-case assumptions, is neglegible compared to the physiological and unavoidable internal EO burden of the organism.

Keywords: Ethylene oxide; Polyglycol ethers; Skin-care products; Risk assessment

Mercury toxicokinetics in Wistar rats exposed to elemental mercury vapour: modeling and computer simulation by I. Falnoga; A. Mrhar; R. Karba; P. Stegnar; M. Škreblin; M. Tušek-Žnidarič (pp. 406-415).

The kinetics of total mercury (Hg) absorption, distribution and elimination in Wistar rats exposed for long periods to elemental mercury vapour (Hg°) in the Idrija mercury mine were studied. From the experimental data base a compartmental model was built as a framework for experimental data interpretation and prediction of organ mercury levels under different conditions. Using the model the exposures of rats under conditions comparable to those of professionally exposed workers (mercury miners, workers in the chloralkali industry) and individuals with amalgam fillings were simulated.

Keywords: Elemental mercury vapour; Rats; Toxicokinetics; Compartmental model; Computer simulation

Tissue and sex-dependent differences in CYP2A activities in hamsters by Päivi Pelkonen; Matti Lang; Markku Pasanen (pp. 416-422).

Three enzymatic activities of the CYP2A subfamily, coumarin 7-hydroxylase (COH), testosterone 15α-hydroxylase (T15αOH) and testosterone 7α-hydroxylase (T7αOH), were characterized in liver, kidney and lung microsomes from control, pyrazole (PYR), 3-methyl-cholanthrene (MC) and phenobarbital (PB) treated female and male Syrian golden hamsters. Sex-dependent changes in the enzymatic activites were found. Among control animals COH and T15αOH activities were higher in males. T7αOH activity was five times higher in female kidneys than in males. Inducers changed this metabolic profile. MC and PB were potent CYP2A inducers in extrahepatic tissues: significant increases were found in COH (5-fold) and T15αOH (12-fold) activities in female MC lung microsomes and T7αOH (7-fold) in MC male kidney microsomes. PB increased significantly activities of COH (5-fold), T15αOH (3-fold) and T7αOH (10-fold) in male kidney microsomes. All inducers significantly increased T7αOH activity in male kidney microsomes but decreased hepatic T7αOH activity in both sexes. PYR treatment decreased hepatic CYP2A activities. Anti-mouse CYP2A4/5 antibody inhibited COH activity by a variable extent depending on the tissue and pretreatment and recognised three 52-, 49-, 48-kDa bands in liver and two major bands in kidney (48 and 49 kDa) and lung (49 and 52 kDa) microsomes. COH and T15αOH activities correlated well with 49 kDa protein (r=0.95 and r=0.99, respectively) in lung microsomes. These results suggest that i) the inducibility and immunological characteristics of CYP2A activities in hamster tissues are clearly different compared with those found in mouse, ii) MC and PB are potent CYP2A inducers in extrahepatic tissues of hamsters, and iii) that extrahepatic CYP2A activities exhibit remarkable tissue- and sex-dependent differences in their response to chemical inducers.

Keywords: Cytochrome P450; Extrahepatic monooxygenases; Induction; Metabolism

Metabolism of dichloromethane (methylene chloride) to formaldehyde in human erythrocytes: influence of polymorphism of glutathione transferase Theta (GST T1-1) by Ernst Hallier; Klaus R. Schröder; Karin Asmuth; Anja Dommermuth; Beate Aust; Hans Werner Goergens (pp. 423-427).

Human hemolysate was incubated in vitro with different concentrations of dichloromethane (methylene chloride). The resulting enzymatically mediated production of formaldehyde was determined by two independent analytical methods (Nash-reaction/colorimetry or HPLC). The formation of formaldehyde from dichloromethane is influenced by the polymorphism of glutathione-S-transferase (GST) Theta, in the same way as the metabolism of methyl bromide, methyl chloride, methyl iodide and ethylene oxide. Three quarters of the population (“conjugators”) possess, whereas one quarter (“non-conjugators”) lack this enzyme activity in human erythrocytes. The metabolism of dichloromethane in hemolysate in vitro can be described by Michaelis-Menten kinetics; for an individual with high GST T1-1 enzyme activity, the maximum velocity of formaldehyde production was calculated to be approximately 180 pmol/min per mg Hb, the k M being approximately 60 mM dichloromethane. Carcinogenicity of dichloromethane in long-term inhalation exposure of rodents has been attributed to metabolism of the compound via the GST-dependent pathway. Extrapolation of the results to humans for risk assessment should consider the newly discovered polymorphic enzyme activity of GST Theta. Furthermore, the possible existence of a “high-risk” population among humans should be considered in epidemiological research.

Keywords: Dichloromethane; Methylene chloride; Formaldehyde; Human erythrocytes; Enzyme polymorphism; Glutathione-S-transferase Theta; Risk assessment

Quantitation of the hydroxyl radical adducts of salicylic acid by micellar electrokinetic capillary chromatography: oxidizing species formed by a Fenton reaction by Masafumi Tomita; Toshiko Okuyama; Satoru Watanabe; Hiroko Watanabe (pp. 428-433).

There has been controversy concerning the products formed by a Fenton reaction. We determined the hydroxyl radical (^•OH) generated in a Fenton reaction system with no iron chelator using micellar electrokinetic capillary chromatography (MECC). The hydroxyl radical generated in this Fenton system attacked salicylic acid to produce major products of 2,3- and 2,5-dihydroxybenzoic acid (DHB), 2,3-DHB being prominent. Hydroxyl radical scavengers, such as mannitol, ethanol, thiourea and a ferric chelator, Desferal, significantly diminished the peaks for DHBs, showing production of ^•OH. We compared the MECC method with the electron paramagnetic resonance (EPR) spin trapping technique. The quantity of DHBs obtained by MECC increased dose-dependently up to 1 μM Fe²⁺ at a fixed concentration of H₂O₂, whereas that of the spin adduct by EPR showed a bell-shaped curve. This quantitation of ^•OH adducts by MECC supports the proposal that the oxidizing species formed by a Fenton reaction with no chelator is ^•OH. The EPR spin trapping method appears to be erroneous, particularly when iron is present at a higher concentration than hydrogen peroxide. The application of this method to the paraquat effect in vitro is demonstrated, and the possibility for analysis of ^•OH in vivo is also discussed.

Keywords: Hydroxyl radical; Fenton reaction; Salicylic acid; Micellar electrokinetic capillary chromatography(MECC); EPR spin trapping; Paraquat

Distribution and reactivity of inhaled ¹⁴C-labeled toluene diisocyanate (TDI) in rats by Amy L. Kennedy; Tami R. Wilson; Maryanne F. Stock; Yves Alarie; William E. Brown (pp. 434-443).

Inhalation exposure to toluene diisocyanate (TDI) can result in a variety of airway diseases. Concern has been expressed that a putative carcinogenic potential of TDI exists as a result of the formation of toluenediamine (TDA) by hydrolysis of the isocyanate in the body. Results from long-term bioassays (TDI inhalation versus gavage in rats and mice) are contradictory and discrepancies do exist concerning the interpretation of adverse effects. This study was performed to analyze the distribution and reactivity of radioactively-labeled TDI using vapor exposure in a rat model system. Rats were exposed to ¹⁴C-TDI vapors at concentrations ranging from 0.026 to 0.821 ppm for 4h. All tissues examined showed detectable quantities of radioactivity, with the airways, gastrointestinal system and blood having the highest levels which increased with exposure concentration. The concentration of radioactivity in the bloodstream after exposure was linear with respect to dose. The majority (74–87%) of the label associated with the blood was recovered in the plasma, and of this, 97–100% of the ¹⁴C existed in the form of biomolecular conjugates. Analysis of stomach contents shows that the majority of the label is also associated with high (>10 kDa) molecular weight species. While a larger percentage (28%) of the label is found in the low molecular weight fraction relative to blood, this low molecular weight labeled material represents at least eight different components. Thus, over the vapor exposure concentrations and time tested, it appears that conjugation is the predominant reaction and that free TDA is not a primary in vivo reaction product under the conditions tested.

Keywords: Toluene diisocyanate; TDI; Radioactive tolyl distribution; Toluenediamine; TDA; In vivo reactivity

Correlation between inflammatory cellular responses and chemotactic activity in bronchoalveolar lavage fluid following intratracheal instillation of nickel sulfate in rats by Seishiro Hirano; Takako Asami; Naomi Kodama; Kazuo T. Suzuki (pp. 444-449).

In a preceding study, we reported that the numbers of macrophages and polymorphonuclear leukocytes (PMN) were increased in bronchoalveolar lavage fluid (BALF) following the intratracheal instillation of nickel sulfate (NiSO₄) in rats. In the present study, BALF chemotactic activities for both macrophages and PMN were measured to investigate if the increases of these inflammatory cells in BALF depend on increases in chemotactic activities in epithelial lining fluid (ELF) of the lung. Both the number of PMN and the PMN chemotactic activity peaked at 2 days post-instillation and they were significantly correlated. However, the PMN chemotactic activity was inversely correlated with concentration of leukotriene B₄ (LTB₄), a well-known chemotaxin. Although PMN were not observed in control BALF, LTB₄ concentration in the control ELF (ca. 5×10⁻⁷ M) was estimated to have a potential to attract PMN chemotactically through a membrane in in vitro migration assay. These results suggest that the presence of LTB₄ in ELF itself does not trigger transpulmonary PMN infiltration. The rat BALF were fractionated by high performance liquid chromatography (HPLC), and PMN chemotactic activity of each fraction was measured. The elution profiles of PMN chemotactic activity showed that there were at least two different chemotaxins in BALF obtained from the NiSO₄-exposed rats. Macrophage chemotactic activity in BALF also peaked at 2 days post-instillation. However, the number of macrophages was not significantly correlated with the chemotactic activity for macrophage in BALF. The HPLC study showed that the macrophage chemotactic substance in the BALF obtained from NiSO₄-exposed rats was different from complement fragment (C5a) and its MW was estimated to be 10–12 kD.

Keywords: Chemotaxis; Alveolar macrophage; Polymorphonuclear leukocyte; Nickel sulfate; Leukotriene B₄

Effect of sodium pyridinethione on the uptake and distribution of nickel in rats, ferrets and guinea-pigs by Kathleen Borg-Neczak; Hans Tjälve (pp. 450-458).

Oral administration of sodium pyridinethione together with Ni²⁺ (using ⁶³Ni²⁺ as a tracer) to rats, ferrets and guinea-pigs produced highly increased tissue levels of the metal in several tissues in comparison with animals given the Ni²⁺ alone. Ni²⁺ forms a lipophilic complex with pyridinethione and it can be assumed that a facilitated passage of the Ni²⁺ across the cellular membranes of various tissues is important for the observed effects. Pigmented tissues (e.g. the eye melanin), the pancreatic islets, the nervous system and striated muscles showed high levels of Ni²⁺ in animals given sodium pyridinethione. However, in some instances marked species differences were observed. Thus, microautoradiography indicated an uptake of Ni²⁺ both in the - and α-cells in the pancreatic islets in the rat, whereas in the guinea-pig only some cells (probably the α-cells) accumulated high levels of Ni²⁺. In the ferret sodium pyridinethione induced a high uptake of Ni²⁺ in the heart muscle, which was not seen in the other species. The Ni²⁺ is probably taken up in the various tissues complexed to pyridinethione. Within the tissues the complex may dissociate and the Ni²⁺ may bind to some endogeneous tissue components. The affinity of the Ni²⁺ for the endogeneous ligands in relation to the affinity for the pyridinethione may be of importance for the effects on the disposition of the Ni²⁺. The species variations may be related to differences in the structural conformations of the endogeneous Ni²⁺-binding ligands.

Keywords: Sodium pyridinethione; Nickel; Rat; Ferret; Guinea-pig

Electrophysiological and biochemical effects following single doses of organophosphates in the mouse by Sean S. Kelly; Elaine Mutch; Faith M. Williams; Peter G. Blain (pp. 459-466).

Single doses of organophosphates (mipafox or ecothiopate) were given subcutaneously to mice. At intervals up to 77 days after dosing animals were killed and muscle action potentials and endplate potentials were recorded intracellularly in mouse phrenic-nerve/hemidiaphragm preparations. Activities of acetylcholinesterase and neuropathy target esterase in brain and acetylcholinesterase in diaphragm were also measured. Mipafox (0.11 mmol/kg), a neurotoxic organophosphate, produced an increase in prejunctional jitter (i. e. the variabilities of the latencies) of endplate potentials. This increase began 14–21 days after administration and lasted more than 23 days. No clinical signs of neuropathy were observed during this study. Mipafox also produced an increase in postjunctional (muscle action potential) jitter. Mipafox inhibited brain and diaphragm acetylcholinesterase and brain neuropathy target esterase. By comparison, a non-neurotoxic organophosphate, ecothiopate (0.5 μmol/kg), was a potent inhibitor of diaphragm acetylcholinesterase and produced a large increase in postjunctional jitter but ecothiopate did not inhibit brain neuropathy target esterase and had no effect on prejunctional jitter. Doses were chosen so that the inhibition of diaphragm acetylcholinesterase by each of the two organophosphates was similar. It is concluded that the neurotoxic organophosphate, mipafox, produced measurable changes in nerve function. These long-term changes may represent a new phenomenon, unrelated to the classical organophosphate induced delayed neuropathy. Alternatively, they may represent a neuropathic process which precedes or is below the threshold for clinical signs.

Keywords: Organophosphates; Mipafox; Ecothiopate; Neurotoxicity; Enzyme activity

Piperonyl butoxide induces hepatocellular carcinoma in male CD-1 mice by O. Takahashi; S. Oishi; T. Fujitani; T. Tanaka; M. Yoneyama (pp. 467-469).

Male CD-1 mice in groups of 52, 53 or 100 were administered piperonyl butoxide (α-[2-(2-butoxyethoxy)ethoxy-4,5-methylenedioxy-2-propyltoluene) in the diet at levels of 0 (control), 0.6 and 1.2% for 12 months. Hepatocellular carcinoma was induced in treated groups in a dose-dependent manner but not in the control group. The incidences of hepatocellular carcinoma were 11.3 and 52.0% in mice given 0.6 and 1.2% piperonyl butoxide, indicating that piperonyl butoxide can cause hepatocellular carcinoma in mice as it is known to do in rats.

Keywords: Piperonyl butoxide; Hepatocellular carcinoma; Hemangiosarcoma; Carcinogenesis; Mice

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Archives of Toxicology (v.68, #7)

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Archives of Toxicology (v.68, #7)