Risk Groups

There are cases that demonstrate differences in individual susceptibility to benzene toxicity. An example is that of a husband and wife who manufactured whistles by dipping plastic material into a bucket of benzene (88.42% and toluene 9.25%). The wife developed severe aplastic anaemia after 6 months, whereas the husband developed no haematological abnormalities even after 14 years of exposure (Baslo and Aksoy, 1982; Aksoy, 1985). This was probably due to genetic differences. This is further supported by reports of a familial connection in some cases of benzene poisoning. Aksoy (1985) described cases of benzene toxicity involving cousins, an uncle and nephew, and a father and son.

Although there are various factors that may make some individuals more likely to develop benzene toxicity (listed below), it is believed that all humans are susceptible to the pancytopenic effects of benzene (ATSDR, 1997).

• Pre-existing bone marrow disease.

Benzene is a bone marrow toxin. Individuals with haematological disease, e.g., beta-thalassaemia, may be more at risk from the toxic effects of benzene (Aksoy et al., 1971). Folic acid deficiency may be a risk factor for megaloblastic erythropoiesis in patients with benzene-induced pancytopenia (Aksoy et al., 1972).

• Rapid synthesis of bone marrow (Marcus, 1990) and high bone marrow myeloperoxidase activity (Snyder, 2000).

Benzene accumulates in bone marrow and individuals rapidly synthesising bone marrow are at greater risk of benzene toxicity (Marcus, 1990). This includes fetuses, infants and individuals with anaemia and related blood disorders.

• Low NAD(P)H:quinone oxidoreductase 1 (NQO1) concentrations (Rothman et al., 1997; Moran et al. 1999; Snyder, 2000).

NQO1 is an inducible enzyme involved in the detoxification of a number of compounds. It is capable of detoxifying quinones (produced by the oxidation of phenolic metabolites of benzene) by maintaining them in their reduced forms. Recently, a polymorphism in NQO1 has been identified and individuals homozygous for this mutation have no NQO1 activity. It has been suggested that such individuals may be more susceptible to benzene toxicity. A study of benzene exposed workers in China supported this hypothesis (Rothman et al., 1997). Moran et al. (1999) suggest NQO1 is induced in human bone marrow cells after exposure to benzene metabolites. They found that induction of NQO1 was not observed in cells of individuals who are homozygous for the mutation. In addition, these individuals are more susceptible to other forms of chemical induced toxicity and cancer. The proportion of individuals with this mutation varies between different ethnic groups. This is a relatively new area of study and many questions have still to be answered (Ross, 1996; Smith, 1999).

• High P450 CYP2E1 activity (see Smith 1996a).

A higher rate of P450 CYP2E1-dependent metabolism will increase the rate of formation of benzene metabolites (Snyder, 2000). In the study by Rothman et al. (1997) CYP2E1 polymorphism did not affect benzene metabolism or influence the risk of benzene poisoning, except in those individuals with high CYP2E1 activity who were also homozygous for the NQO1 mutation (see above).

• Low GSH transferase concentrations (Snyder, 2000).

Glutathione (GSH) is involved in the detoxification of many substances. GSH transferase is responsible for catalysing the reaction converting GSH to GS-. A low concentration of GSH transferase will delay detoxification.

It should be noted however, that the relative activities of these enzymes (CYP2E1, NQO1, GSH transferase, bone marrow myeloperoxidase) determines an individual's susceptibility to benzene toxicity since there may be compensation. For example, an individual with a high concentration of NQO1 combined with a high CYP2E1 activity may not be more susceptible to benzene toxicity (Snyder, 2000).

It has long been suggested that women may be more susceptible to benzene toxicity (Barlow and Sullivan, 1982). Data from physiological-based pharmacokinetic (PBPK) modelling supports this. Although females have lower blood benzene concentrations under the same exposure conditions than males, they metabolise a greater percentage (23-26% difference). Consequently, they may be exposed to higher concentrations of benzene metabolites (Brown et al., 1998). A number of observations support this. In the study by Liu et al. (1996) the concentration of peripheral lymphocyte 8-hydroxy-2-deoxyguanosine (a measure of DNA oxidative damage) was higher in females compared to males when exposed to the same benzene concentration. However, there was no difference in the 8-hydroxy-2-deoxyguanosine concentration, lymphocyte micronuclei (a measure of genotoxicity) or leucocyte count (a measure of myelotoxicity) between males or females in the control group.

No gender differences in haematopoietic and lymphoproliferative cancers were observed in Chinese workers exposed to benzene, although the number of leukaemias and other diseases was small (Li et al., 1994).

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