Adduct levels, correlation with

Laboratory animal experiments demonstrate that dose-response relationships exist between carcinogen exposure and adduct levels, suggesting the utility of these studies In human exposure assessments. In animals, DNA and protein adduct levels correlate with dose of PAHs (63-65). tobacco-smoke condensate (43.60.66). H-nltrosamlnes (67-70). aromatic amines (21) (Beland, F. A., unpublished data Poirier, M. C., unpublished data) and heterocyclic amines (72.73). 

Acetaminqihen adducts with protdn, detection in humans, 324/,325,329-334 immumdiemical quantification of adducts, 3163W.319 loxid studies, 329-334 N-Ace transferase, identification of aoetylatorpheiwtype, 198 Acquired genetic abnormalities, 198 Adduct levels, correlation with cardnogenic incidence, 195 Affinity chtDmatogta, antibody requirements, 4... 

Exposure. The presence of the -hexane metabolite 2,5-hexanedione in the urine is a reasonably reliable marker for exposure to -hexane and has been correlated with air concentrations in the workplace. This is not a specific marker since 2-hexanone is also metabolized to 2,5-hexanedione. The levels of this metabolite in the urine associated with neurotoxicity are not known. A more sensitive marker for exposure may be the presence of pyrolidated proteins in the blood or hair, a result of the reaction of 2,5-hexanedione with the side-chain amino group of lysine (Graham et al. 1995 Johnson et al. 1995). These methods have only been tested after oral exposure to 2,5-hexanedione in the rat model. It would be very useful to know if measurement of pyrrole adducts or cross-linked proteins is also feasible after inhalation exposure to u-hexane in the rat model. Further development and validation of this method in an occupationally exposed population may then be useful. 

Effect. There are no specific disease states in humans or animals that have been associated with exposure to 3,3 -dichlorobenzidine. Hemoglobin adducts have been isolated from the blood of 3,3 -dichlorobenzidine-treated animals (Bimer et al. 1990 Joppich-Kuhn et al. 1997). It is not known what relationship exists between adduct levels in the blood and 3,3 -dichlorobenzidine toxicity. Further research in animal models is needed to determine if these adducts could be correlated with effects of 3,3 -dichlorobenzidine exposure. Further studies to identify more sensitive toxic effects (noncancer) that are specific for 3,3 -dichlorobenzidine would be useful in monitoring effects in people living near hazardous waste sites containing 3,3 -dichlorobenzidine. 

Q. Zhou, G. Talaska, M. Jaeger, V.K. Bhatnagar, R.B. Hayes, T.V. Zenser, S.K. Kasyap, V.M. Lakshmi, R. Kashyap, M. Dosemeci, F.F. Hsu, D.J. Parikh, B. Davis, N. Rothman, Benzidine-DNA Adduct Levels in Human Peripheral White Blood Cells Significantly Correlate with Levels in Exfoliated Urothelial Cells , Mut. Res., 393,199-205 (1997). 

By using leukocytes from chemotherapy patients with squamous-cell carcinoma of the head and neck region, it was demonstrated that damage removal from DNA was related to cisplatin resistance [83], This type of study assumes the profile of adduct formation and repair to be the same in peripheral and tumor tissue. The hypothesis was supported by several early studies which employed either atomic absorption spectroscopy or immunochemical techniques to demonstrate a relationship between DNA adduct formation in blood cells and disease response [84-89]. Subsequent work revealed, however, that cisplatin-DNA adduct levels do not always correlate with survival [90] and can vary substantially between individuals [91]. 

A number of mechanisms allow a cell to become resistant to cisplatin. The most commonly acknowledged ones include decreased drug uptake [16], increased levels of sulfur-containing macromolecules reacting with cisplatin [17], and increased DNA repair [18]. Increased tolerance to cisplatin adducts may also play a role in the appearance of a resistant phenotype. This is as suggested by data obtained in some ovarian carcinoma cells in which resistance is accompanied by a reduced rate of adduct removal when compared to the sensitive parental cell-line [19]. The molecular mechanism of this phenomenon is unknown but has been correlated with an increased replicative bypass of platinum-DNA adducts. 

Functionally, phagocytosis of HZ has been reported to impair macrophage oxidative burst, to downregulate iNOS activation, and to perturb cytokine profiles in infected patients. It has also been shown to correlate with increased levels of immunomodulatory LPO products such as prostaglandin E2 (PGE2), HNE, and HETEs (40) in monocytes. The biologic activity of these compounds is generally derived from either of two mechanisms. In the first mode of action, the reactive intermediates or products may form adducts to DNA or proteins. Thus, a variety of... 

Hydroxypyrene was measured in the urine, and PAH-DNA adducts were measured in white blood cells to demonstrate their relationship to the exposure. Results from these workers were compared to two reference control groups research and development (R D) workers and nickel refinery workers. Mean values of PAH-DNA adducts in the white blood cells from randomly selected participants in the three groups were only marginally different, with the exception of two smokers in the electrode plant, who had the highest levels. Mean PAH-DNA adduct levels were 10.9 adducts per 108 nucleotides for the electrode workers, 10.8 adducts per 10 nucleotides for the R D personnel, and 10.0 adducts per 10 nucleotides for nickel plant workers not occupationally exposed to PAHs. No correlation was found between PAH-DNA adducts and 1-hydroxypyrene in the urine. 

Van Schooten FJ, Hillebrand MJX. Van Leeuwen FF, et al. 1992. Polycyclic aromatic hydrocarbon-DNA adducts in white blood cells from lung cancer patients No correlation with adduct levels in lung. Carcinogenesis 13(6) 987-993. 

The role of depurinating adducts and apurinic sites in the PAH-induced cancer process is controversial and has yet to be fully elucidated. There are lines of evidence that both support and refute this theory. In support of this theory, the levels of depurinating adducts of B[a]P correlated with mutations in the H-ras oncogene in DNA isolated from mouse skin papillomas initiated by this compound (Chakravarti et al. 1995). It is well known that the initiation of skin tumors in mice is associated with the formation of mutations in the H-ras gene [reviewed by Ross and Nesnow (1999)]. DB[a,/]P treatment of mouse skin forms papillomas which contain the H-ras codon 61 (CAA to CTA) mutation. These same mutations were induced in early preneoplastic skin within one day after DB[a,/]P treatment and appear to be related to DB[a,/]P-Ade-depurinating adducts. Studies have shown that apurinic... 

Ross, J. A., Nelson, G. B., Wilson, K. H., Rabinowitz, J. R., Galati, A., Stoner, G. D., Nesnow, S., and Mass, M. J. (1995). Adenomas induced by polycyclic aromatic hydrocarbons in strain A/J mouse lung correlate with time-integrated DNA adduct levels. Cancer Res 55, 1039-1044. 

Ottender, M., and Lutz, W. K. (1999). Correlation of DNA adduct levels with tumor incidence carcinogenic potency of DNA adducts. Mutat Res 424, 237-247. 

Polycyclic aromatic hydrocarbons are capable of forming adducts with DNA in cells. Exposure to PAHs from creosote were measured in the personal work areas of coke oven workers in the Czech Republic (Lewtas et al. 1997). Measured levels of DNA adducts in white blood cells of a nonoccupationally exposed population were well correlated with the low to moderate environmental exposures. The DNA adducts of the coke oven workers who were exposed to carcinogenic PAHs at levels of <5->200,000 ng/m3 (<0.005->200 pg/m3) did not correlate well with the exposure levels. These authors concluded that various mechanisms were responsible for the lower DNA-binding potency at the higher exposure levels, precluding the use of a linear model for dose-response extrapolation in risk assessment. 

Reddy MV, Blackburn GR, Schreiner CA, et al. 1997. Correlation of mutagenic potencies of various petroleum oils and oil coal tar mixtures with DNA adduct levels in vitro. Mutat Res 378 89-95. 

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