Benzene, toxicity

NADPH quinone oxido-reductase 1 Pro187Ser variant occurring with about 5% frequency is functionally almost completely deficient. Impaired activity associated with benzene toxicity and cancer chemotherapy induced leukemia. 

Snyder, R., et al., Metabolic correlates of benzene toxicity, in Biological Reactive Intermediates, Snyder, R.e.a., Eds., Plenum Press, New York, 1982. 

Seaton MJ, Schlosser PM, Medinsky MA. 1995. In vitro conjugation of benzene metabolites by human liver Potential influence of interindividual variability on benzene toxicity. Carcinogenesis 16 1519-1527. 

Goldstein BD Hematotoxicity in humans. In Laskin S, Goldstein BD Benzene toxicity. A critical evaluation. J Toxicol Environ Health Swpp/2 69-105, 1977... 

Caution. The reaction should be carried out in a well-ventilated hood because carbon monoxide—a highly toxic, colorless, and odorless gas—is used in large amounts in this reaction and benzene—toxic and also possibly carcinogenic—is formed in the reaction. 

Catechol may be oxidized by peroxidases to the reactive intennediate benzo-1,2-quinone, which readily binds to proteins (Bhat et al., 1988) this process, catalysed by rat or human bone-marrow cells in the presence of H2O2 (0.1 mM), is stimulated by phenol (0.1-10 mM), and decreased by hydroquinone and by glutathione, which conjugates with benzo-l,2-quinone. These phenols (phenol, catechol and hydroquinone) may play a role in benzene toxicity to bone marrow all three are formed as benzene metabolites (Smith et al., 1989) and they interact in several ways as far as their bioactivation by (myelo)peroxidases is concerned (Smith et al., 1989 Subrahmanyam et al., 1990). 

Neun, D.J., Penn, A. Snyder, C.A. (1992) Evidence for strain-specific differences in benzene toxicity as a function of host target cell susceptibility. Arch. Toxicol., 66, 11-17... 

Smith, M.T.. Yager, J.W., Steinmetz, K.L. Eastmond, D.A. (1989) Peroxidase-dependent metabolism of benzene s phenolic metabolites and its potential role in benzene toxicity and carcinogenicity. Environ. Health Perspecl., 82, 23-29... 

Tunek, A., Hogstedt, B. Olofsson, T. (1982) Mechanism of benzene toxicity. Effects of benzene... 

Ross, D. (1996) Metabolic basis of benzene toxicity. Eur. J. Haematol, SI (Suppl.), 111-118 Saito, T. Takeichi, S. (1995) Experimental studies on the toxicity of lithographic developer... 

Tunek, A., Hflgstedt. B. Olofsson, T. (1982) Mechanism of benzene toxicity. Effects of benzene and benzene metabolites on bone marrow cellularity, number of granulopoietic stem cells and frequency of micronuclei in mice. Chem.-biol. Interact., 39, 129-138... 

Plappert, U., Barthel, E. Seidel, H.J. (1994) Reduction of benzene toxicity by toluene. Environ, mol. Mutag., 24, 283-292... 

Discuss these reactions in terms of their significance for benzene toxicity and toxicological chemistry, phase I reactions, phase II reactions, and other aspects pertinent to benzene s effects on the body. 

What are the chronic toxicological effects of benzene What kinds of blood abnormalities are caused by benzene exposure How does benzene toxicity affect white cell count How does it affect bone marrow ... 

Earlier work by Schultz (1999) examined the toxicity (log (IGC50) I) of a heterogeneous series of 218 substituted benzenes (200 benzenes for training and 18 for external validation). Because of the use of a different algorithm for the determination of Amjx values, previously reported data on benzene toxicity were re-evaluated. The data for toxicity along with hydrophobicity and newly calculated electrophilicity are reported in Table 12.1. Toxicity values varied uniformly over four orders of magnitude (from -1.13 to 2.82 on a log scale). Hydrophobicity varied over about six orders of magnitude (from -0.55 to 5.76 on a log scale). Reactivity measured by A,nax varied on a linear scale from 0.280 to 0.385. 

Another study revealed effects, ranging from mild to severe, of benzene exposure in factory workers in China (Yin et al. 1987c). The primary activities in these factories were the manufacture of paints, shoes, rubber, leather, and/or adhesives (Yin et al. 1987c). Of the 528,729 workers, 95% were exposed to mixtures of benzene, toluene, and xylene, while 5% (26,319 workers) were exposed to benzene alone at 0.02-264 ppm in air in 95% of the work stations. Over half of the work stations had levels of benzene in the air of less than 13 ppm about 1% had levels of 13-264 ppm. Benzene toxicity, as indicated by leukopenia (leukocyte <4,000/mm3), aplastic anemia, and leukemia, was seen in 0.94% of the workers exposed to benzene and 0.44% of the workers exposed to the mixtures. Similar toxicity was found in employees of 28 of the 141 shoe factories studied (124 cases in 2,740 employees) (Yin et al. 1987c). A positive correlation was observed for prevalence of adverse benzene effects and benzene concentration in data from these 28 shoe factories. The authors determined that the affected people were exposed to benzene concentrations >29 ppm. In one workshop, there were 4 cases of aplastic anemia in 211 workers. These workers were exposed to benzene at a mean concentration of 324 ppm during an 8-month period of employment. The prevalence of aplastic anemia in the shoe-making industry was about 5.8 times that in the general population. The main limitation of this study is the lack of information on the duration of exposure. 

Strengths and Limitations of the Medinsky Model. The Medinsky model has many aspects which are desirable in a PBPK model. It uses more than one route of administration, it uses a range of concentrations and doses, it uses more than one species, and it specifically addresses the production of toxic metabolites, the putative agents of damage in benzene toxicity. However, the model is limited by the fact that it does not predict data other than that on which it was modeled very accurately (Bois et al. 

Benzene toxicity has been studied extensively, and the current understanding of benzene toxicity includes its metabolic fate, mechanism of toxicity, pharmacokinetic models for disposition, and impact of exposure on human health. These aspects of benzene toxicity will be addressed in the following sections. 

Detailed discussion of the proposed mechanisms of benzene toxicity is beyond the scope of this profile. However, the work of Snyder and Kalf (1994) in reviewing benzene toxicity can be summarized, in part,... 

Recent PBPK models have tried to address benzene metabolism in an effort to derive animal-to-human extrapolations (Bois et al. 1991a Medinsky 1995 Medinsky et al. 1989a Spear et al. 1991 Travis et al. 1990). Each model described a multicompartmental model that attempted to relate the generation of metabolites to end points of benzene toxicity. The generation of hydroquinone and muconaldehyde in the liver, with further metabolism in the bone marrow, has been addressed as well as the available data allow. However, the model is not sufficiently refined to allow it to accurately predict human metabolism. Thus, although PBPK modelling has provided a means to improve animal to human extrapolations, the models need to be improved. 

There is general agreement among various investigators in the field of benzene toxicity that benzene metabolites, rather than benzene, are the primary toxic agents in the induction of hematotoxicity. This agreement has evolved as a result of studies in which agents known to alter benzene metabolism (toluene, phenobarbital, and ethanol) have also altered benzene toxicity (Andrews et al. 1977 Sammett et al. 1979). 

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