Haemoglobin adducts

Table 4. Air and urine levels and haemoglobin adduct levels measured in 1990 among chemical workers employed at a plant where excess bladder cancer incidence was observed...

Gaigas et al. (1995) have developed a physiological toxicokinetic model of acrylonitrile in rats which includes the behaviour of CEO. In-vitro kinetic studies of the metabolism of both acrylonitrile and CEO showed that epoxidation to CEO is saturable, while glutathione conjugation of acrylonitrile follows first-order kinetics. The model combines these kinetic parameters with tissue partition data to allow simulation of the urinary excretion of acrylonitrile metabolites and the fonnation of haemoglobin adducts (see below). The model has been further refined by Kedderis et al. (1996) to predict the behaviour of acrylonitrile and CEO after inhalation exposure to acrylonitrile. 

Acrylonitrile forms adducts with proteins and glutathione. It also forms DNA adducts in vitro, but only after cytochrome P450 bioactivation, most likely through its epoxide metabolite (cyanoethylene oxide), which is also formed in vivo. Acrylonitrile-haemoglobin adducts have been detected in exposed workers. 

A, B, U metabolites in exhaled air, blood, urine, respectively CYP, cytochrome P450 GST, glutathione-S-transferase EH, epoxide hydrolase dashed frame metabolites forming DNA or haemoglobin adducts [ ] proposed metabolites not yet detected dashed lines, assumed pathways number assignment according to Nauhaus et al. (1996)... 

In the model of Csanady et al. (1996), the biochemical parameters for butadiene in rats and mice were obtained by fitting model simulations to in-vivo data of Bolt et al. (1984) and Kreiling et al. (1986). The biochemical parameters for epoxybutene were identical to those of Johanson and Filser (1993, 1996). This model accurately predicted experimental data on epoxybutene. The most advanced models are those of Csanady etal. (1996) and Sweeney et al. (1997), since they can simulate both epoxybutene and diepoxybutane as metabolites of butadiene. The tissue blood partition coefficients for diepoxybutane were estimated by Csanady et al. (1996) to have a value of 1 for all tissues. Sweeney et al. (1997) obtained tissue blood partition coefficients from in-vitro measurements (Table 23). Both models yielded good predictions for mice and rats for both metabolites. For humans, no measured data have been reported against which the predictions could be validated. In addition, the model of Csanady et al. (1996) predicted accurately the measured haemoglobin adduct levels (Osterman-Golkar etal., 1993 Albrecht et al., 1993) of epoxybutene in rodents following exposure to butadiene. None of the models published has included the fonnation and elimination of epoxybutanediol. 

Csanady, G.A., Kreuzer, P.E., Baur, C. Filser, J.G. (1996) A physiological toxicokinetic model for 1,3-butadiene in rodents and man blood concentrations of 1,3-butadiene, its metabolically formed epoxides, and of haemoglobin adducts—relevance of glutathione depletion. Toxicology, 113, 300-305... 

Ostennan-Golkar, S.M., Bond, J. A., Ward, J.B., Jr Legator, M.S. (1993) Use of haemoglobin adducts for biomonitoring exposure to 1,3-butadiene. In Sorsa, M., Pcltonen, K., Vainio, H. Henuninki, K., eds, Butadiene and Styrene Assessment of Health Hazards (lARC Scientific Publications No. 127), Lyon, lARC, pp. 127-134... 

Ostennan-Golkar, S., Pcltonen, K., Anttinen-Klemetti, T., Landin, H. H., Zorcec, V. Sorsa, M. (1996) Haemoglobin adducts as biomarkers of occupational exposure to 1,3-butadiene. Mutagenesis, 11, 145-149... 

Perez, H.L., Lahdetie, J., Landin, H.H., Kilpelainen, I., Koivisto, P, Peltonen, K. Osterman-Golkar, S. (1997) Haemoglobin adducts of epoxybutanediol from exposure to 1,3-butadiene or butadiene epoxides. Chem.-biol. Interact., 105, 181-198... 

Noort, D., Fidder, A., Hulst A.G., De Jong L.P., Benschop, H.P. (2000). Diagnosis and dosimetry of exposiue to sulfur mustard development of a standard operating procedure for mass spectrometric analysis of haemoglobin adducts exploratory research on albumin and keratin adducts. J. Appl. Toxicol. 20 SI 87-92. 

Wang SW, Chu CY, Hsu JD, and Wang CJ (1993) Haemo-toxic effect of phenylurea herbicides in rats Role of haemoglobin-adduct formation in splenic toxicity. Food and Chemicals Toxicology 31 285-295. 

Richter, E. and Branner, B., Biomonitoring of exposure to aromatic amines haemoglobin adducts in humans, J. Chromatogr., 778, 49-62, 2002. 

Quantitative Aspects. Ehrenberg and co-workers have proposed that the assay of haemoglobin adducts may provide a suitable although indirect method for the determination of... 

Magagnotti, C., Orsi, F., Bagnati, R., Celli, N., Rotilio, D., Fanelli, R., and Airoldi, L. 2000. Effect of diet on serum albumin and haemoglobin adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in humans. Int. J. Cancer 88 1-6. 

An accidental exposure of six workers to ethylene oxide showed that haemoglobin adducts can be used for long-term exposure surveillance as well as evaluating short-term exposure incidents... 

Table 6 Haemoglobin Adducts Positively Identified by GC-MS in Humans...

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