Handbook of Solvents - George Wypych - ChemTech - Ventech!

1378 Nachman Brautbar
posure to benzene as a causative factor. In this same paper, Golomb et al. 18 looked at the
chromosomal changes of patients treated with chemotherapeutic agents for other malignancies.
Essentially, they looked at a secondary leukemia developing as a result of alkylating
agents. For some reason, they have proposed that losses of part or all of chromosomes numbers
5 and 7 are the specific change resulting from mutageneses, leukemogeneses associated
with various chemicals including insecticides, petroleum products and alkylating
agents.
While this interpretation is compatible with the various animal studies, as well as observations
in patients, there is certainly a lack of scientific connection between the benzene
exposed chromosomal changes, and the chromosomal changes reported in patients treating
with alkylating agents.
Smith, in a recent paper 36 suggested that oxidation of benzene to multiple metabolites
plays a role in producing benzene induced toxicity of DNA damage in bone marrow, and
adds further weight to the hypophysis that multiple metabolites are involved in benzene toxicity.
They also described DNA changes which have been shown to be cause-point mutation.
The investigators measured mutation frequency in 24 workers heavily exposed to
benzene, and 23 matched controls. They found that benzene caused a highly significant increase
in one variant of mutation, suggesting that benzene produces gene duplicating mutations,
but no gene inactivating ones. They suggested that the most-likely consequence of
aberrant recombination caused by benzene metabolites is the production of stable chromosomal
translocation. Indeed, there are several chromosomal abnormalities shown in leukemic
cells. This includes Philadelphia chromosome which results from reciprocal
translocation between chromosome 9 and 22, and has been associated with chronic myeloid
leukemia, and reciprocal translocation between chromosomes 8 and 21. From these studies
it is concluded that benzene is a genotoxic carcinogen, but that other genetic phenomena
may mediate benzene induced hematopoietic toxicity. Based on the available data up to
date, it is proposed 36 that benzene is a carcinogen that does not produce cancer through simple
gene mutations, but rather through a separate class of carcinogens (metabolites of benzene)
that act by a similar mechanism.
In summary, the studies in experimental animals, in vitro, and patients show that benzene
and a wide range of organic solvents are associated with changes in chromosomes and
DNA adducts. While these changes may be helpful in epidemiological studies, the absence
or presence of genetic changes or DNA adducts, cannot be used in a specific case to rule out
or establish causation. The biomarkers described in this chapter in the form of genetic
biomarkers, can be helpful in identifying individual susceptibility, and in some cases understanding
of the mechanism of the disease process. They have a significant number of limitations,
and these include measurements, errors and confounding factors.
REFERENCES
1 Biomarkers: Medical and Workplace Applications, Medelson ML, Moor LC and Peeters JP (eds), John
Henry Press, Washington, D.C., (1998)
2 Rowley JD and Potter D, Blood, 47:705, (1976)
3 Mitelman F, Brandt L and Nilsson PG, Blood, 52(6):1229-1237, (December 1978)
4 First International Workshop on Chromosomes in Leukaemia: Chromosomes in acute non-lymphocytic
leukaemia. Br J Haematol, 39:311, (1978)
5 Golomb HM, Vardiman J and Rowley JD, Blood, 48:9, (1976)
6 Nilsson PG, Brandt L and Mitelman R, Leukemia Res, 1:31, (1977)
7 Mitelman F, et al., Science, 176:1340, (1972)