Ultimate carcinogens

All carcinogens Ultimate carcinogens Procarcinogens Noncarcinogens Unknown carcinogenicity... 

Neither the mechanism by which benzene damages bone marrow nor its role in the leukemia process are well understood. It is generally beheved that the toxic factor(s) is a metaboHte of benzene (107). Benzene is oxidized in the fiver to phenol [108-95-2] as the primary metabolite with hydroquinone [123-31-9] catechol [120-80-9] muconic acid [505-70-4] and 1,2,4-trihydroxybenzene [533-73-3] as significant secondary metabolites (108). Although the identity of the actual toxic metabolite or combination of metabolites responsible for the hematological abnormalities is not known, evidence suggests that benzene oxide, hydroquinone, benzoquinone, or muconic acid derivatives are possibly the ultimate carcinogenic species (96,103,107—112). 

Alternative pathways of activation of nitrosamines, including 3-hydroxylation followed by sulfate conjugation and the formation of alkoxydiazen-ium ions are discussed. The formation of alkyldiazo-nium ions from trialkyltriazenes is presented to show that the formation of the putative ultimate carcinogens from nitrosamines can be studied in a system not requiring metabolic activation,... 

Determination of environmental carcinogens is not an end in itself. Although often misunderstood or misinterpreted, the aim of scientific work in this area is to collect data on human exposure, to pinpoint emission and immission sources and to determine the causes of potential health risks to humans. The ultimate aim is always elimination or reduction of human exposure and thereby prevention of human cancer. In view of the slow progress in the treatment of human cancer this approach is an important strategy in the fight against this disease. 

Kon, S.H. (1978). Biological autoxidation. 1. Decontrolled iron an ultimate carcinogen and toxicant an hvpothesis. Med. Hvpoth. 4, 445-471. 

Methylcholanthrene (3-MC) is a potent carcinogen, intermediate in activity between DMBA and BP (27,77). It was first prepared in 1925 by Wieland from desoxycholic acid (89). Biological studies have tentatively identified the 9,10-dihydrodiol (24a) and/or its 1- or 2-hydroxy derivatives (24b and 24c) and the corresponding diol and triol epoxides (25 -c) as the proximate and ultimate carcinogenic forms, respectively, of 3-MC (90-93). 

Identification of the chemical nature of these adducts is, however, possible only by chromatographic comparison with standards prepared by reacting the ultimate carcinogens with DNA. Proof of identity by co-chromatography should be undertaken using several chromatographic systems which depend for their separation upon different properties of the adduct molecules derivatization prior to reanalysis may be included. 

Many variations on the assay exist, but the ELISA, shown schematically below, is currently highly favored because of its simplicity once established in a laboratory sensitivity, detecting about one adduct per 107 bases and ability to screen many samples because of easy automations. The current prerequisite for the assay is that DNA can be modified to sufficiently high levels with the ultimate carcinogen to make it suitably antigenic. These types of antigens have been used to raise polyclonal antibodies in rabbits (41) and monoclonal antibodies from mice (42). 

Studies on the comparative abilities (13) of B[a]P metabolites to bind to DNA in microsomal systems showed that the 7,8-dihydrodiol was the most efficient. This led to the proposal (69) that dihydrodiol epoxides were the ultimate carcinogenic metabolites. Chemical synthesis of all possible isomers (70.71) has allowed complete structural identification of the adducts (72-74). 

Areas in which additional information is still needed relates to the role and relative importance of different adducts and the mechanisms by which they initiate cells. General principles are developing which will allow better predictions to be made at each of the stages of chemical carcinogenesis outlined in Table I. The ultimate goal therefore, would be, by a combined analysis of all these steps, to predict accurately the carcinogenicity of newly discovered or untested PAH derivatives. 

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