A Physiologically Based Description of Ethylene Oxide Dosimetry in the Rat: Krishnan, Kannan ;Gargas, Michael L. ;Fennell, Timothy R. ;Andersen, Melvin E.
doi: 10.1177/074823379200800301pmid: 1502695
A physiologically based pharmacokinetic (PB-PK) model providing a quantitative description of ethylene oxide (ETO) dosimetry in the rat was developed by integrating information on physiology, tissue solubility of ETO, and rate constants for ETO metabolism and binding. The PB-PK model consisted of nine compartments; liver, lung, testis, brain, fat, venous blood, arterial blood, richly perfused and poorly perfused tissues. The tissue: air partition coefficients of ETO, determined by vial equilibration, were similar among the various tissues (range 44–83). The rate constants for glutathione (GSH) conjugation, hydrolysis, and hemoglobin (Hb)- and DNA- binding were estimated from published data and by conducting in vivo inhalation exposure studies. The model adequately predicted the concentrations of Hb and DNA adducts, hepatic and extrahepatic GSH, and urinary N-acetyl-S-(2-hydroxyethyl)-cysteine following inhalation exposures of 1.2 to 1,200 ppm and intravenous administration of 1 to 100 mg/kg of ETO in male Fischer-344 and Sprague-Dawley rats. There was no evidence of nonlinearity in the overall elimination of ETO in the dose range examined. However, nonlinearities in the components of this first order elimination process (namely GSH conjugation, hydrolysis, exhalation) were found to occur at high exposure concentrations. Characterization of the individual metabolic pathways that affect the tissue dosimetry of ETO is important for interspecies extrapolation and risk assessment for this chemical.
Toxicological Investigations in the Semiconductor Industry: I. Studies on the Acute Oral Toxicity of a Complex Mixture of Waste Products from the Aluminium Plasma Etching Process: Bauer, Siegfried ;Wolff, Ilona ;Werner, Nadeshda ;Hoffmann, Peter ;Herzschuh, R. ;Oemus, Kerstin ;Rath, Friedrich Wilhelm ;Voigt, Reiner
doi: 10.1177/074823379200800302pmid: 1386950
In dry etching processes—one of the sources of potential exposure to toxic wastes in the semiconductor industry—complex mixtures of inorganic and organic compounds arise from reactions between feed stock gases (BCl3/Cl2), top layers (aluminium, photoresist), and the carrier gas (N2). Two different fractions of the complex mixture—one an ethanolic solution (ES) and the other an insoluble liquid residue (LR)—were examined for acute oral toxicity in rats. Analytical data showed that the ethanol soluble fraction contained mainly inorganic compounds, whereas the residue contained various halogenated hydrocarbons. Neither death nor behavioral changes occurred after oral administration and observation up to 23 days. ES caused a lower mean arterial blood pressure in both sexes, increased P-R-intervals in male rats, and caused some mild biochemical and hematological alterations and changes in relative organ weights compared to the control groups. Exposure to LR influenced food and water intake, and caused a significant decrease in body weights, signs of polyurie, as well as changes in various relative organ weights and biochemical and hematological parameters. The blood pressure of the male animals fell and the heart rates of both sexes decreased.
Indication of Dna Strand Breaks in Human White Blood Cells after In Vitro Exposure to Toluene Diisocyanate (TDI): Marczynski, Boleslavv ;Czuppon, Adam B. ;Marek, Wolfgang ;Baur, Xaver
doi: 10.1177/074823379200800303pmid: 1323884
Toluene diisocyanate (TDI), used expecially for the production of polyurethanes, is known to induce chromosome aberrations, base-pair substitution, and frameshift mutation after metabolic activation. Following treatment of human blood by TDI, the isolated DNA was analyzed by anion-exchange chromatography (FPLC) before and after denaturation. In addition, DNA from white blood cells was analyzed by alkaline and neutral filter-elution and pulsed-field gel electrophoresis (PFGE). The results show that TDI induced single-and double-strand breaks in the DNA of white blood cells in vitro. The elution rate, calculated after alkaline filter elution, was significantly increased after TDI treatment. An average size of the TDI-induced DNA fragments was estimated by PFGE to be smaller than 250 kb. Denaturation and renaturation of TDI-treated DNA indicated that DNA could be cross-linked by TDI. Purified DNA treated with TDI in buffer alone does not induce DNA fragments as shown by FPLC. These findings indicate that DNA damages are induced by TDI after the biotransformation of TDI. The results show that TDI exposure induces DNA damage of white blood cells in vitro.
On Reference Dose (RFD) and Its Underlying Toxicity Data Base: Dourson, Michael L. ;Knauf, Linda A. ;Swartout, Jeffrey C.
doi: 10.1177/074823379200800304pmid: 1502696
The toxicity data of pesticides were summarized and compared amongst different animal species and types of bioassays. These comparisons showed the expected inter-species and inter-bioassay variability. After quantitative and statistical analysis of these data, it was concluded that, on the average, a 2-year dog bioassay detected toxic responses at similar doses as a 2-year rat study, and that both of these bioassays detected toxic responses at lower doses than either a rat 2-generation bioassay, a rat developmental toxicity study, or a 2-year mouse bioassay. Although these chronic dog and rat bioassays were found to detect toxic responses at lower doses than the other studies listed, this analysis does not reflect the seriousness of the effects that were compared. Within the confines of this analysis, then, it appears that a 2-year dog and rat study, reproductive and developmental bioassays are a sufficient data base on which to estimate high confidence Reference Doses (RfDs), and furthermore, that an additional uncertainty factor is needed to estimate RfDs to account for this inter-species and inter-bioassay variability when fewer than this number of bioassays are available.
Effects of Hexachloro-1,3-Butadiene and 1,1,2,2-Tetrachloroethylene on Individual Serum Bile Acids: Bai, Cheng-Long ;Canfield, Paul J. ;Stacey, Neill H.
doi: 10.1177/074823379200800305pmid: 1502697
Rats were exposed to hexachlorobutadiene (HCBD) or tetrachloroethylene (TET) in order to determine which of these chemicals was more likely to be responsible for elevations in individual serum bile acids (SBA) found in workers exposed primarily to these two chemicals. Increases in cholic and taurocholic acids were found on exposure to high doses of HCBD. Elevations of SBA occurred right down to low exposures for TET, however, with cholic, chenodeoxycholic, and glycocholic acids being the most sensitive bile acids. Only at high doses for each chemical was there any indication of liver injury as determined by routinely used parameters such as serum enzymes or bilirubin. The data suggest that TET is likely to play a role in the elevated individual SBA in an exposure situation where both this chemical and HCBD are found.