Carcinogenic activity determination

It is of interest to compare the shapes and sizes of various molecules with appreciable carcinogenic activity. For example, aflatoxin B] (VI), found in moldy peanuts and grain, is one of the most powerful carcinogens known. Its crystal structure was determined by van Soest and Peerdeman (46-48). 

This list includes BP, 7,12-dimethylbenz[a]anthracene, 3-methylchol-anthrene, dibenzo[a,i]pyrene and dibenzo[a,h]pyrene. These PAH can be activated both by one-electron oxidation and/or monooxygenation. There are a few PAH with low IP which are inactive (Table I), such as perylene, or weakly active, such as anthanthrene. This indicates that low IP is a necessary, but not sufficient factor for determining carcinogenic activity by one-electron oxidation. These inactive or weakly active PAH have the highest density of positive charge delocalized over several aromatic carbon atoms in their radical cations, whereas the active PAH with low IP have charge mainly localized on one or a few carbon atoms in their radical cations. 

NTP determined that there was clear evidence of carcinogenicity in male rats based on the increased incidence of renal neoplasms and no evidence of carcinogenic activity in female rats (NTP 1989). The EPA classified hexachloroethane as a possible human carcinogen (Group C). The slope factor calculated by EPA is 1.4xl0 2 (mg/kg/day) 1 for both the oral and inhalation routes of exposure (IRIS 1995). IARC has determined that hexachloroethane is not classifiable as to human carcinogenicity (Group 3). 

A nonlinear approach should be selected when there are sufficient data to ascertain the mode of action and to conclude that it is not linear at low doses, and the agent does not demonstrate mutagenic or other activity consistent with linearity at low doses. The POD is in this case generally a BMDL when incidence data are modeled. A sufficient basis to support this nonlinear procedure is likely to include data on responses that are key events in the carcinogenic process. This means that the POD may be based on these precursor response data, for example hormone levels or mitogenic effects, rather than tumor incidence data. A nonlinear approach can be used to develop an RfD or an RfC. This approach expands such reference values, previously reserved for threshold effects, to include carcinogenic effects determined to have a nonlinear mode of action. A nonlinear approach should generally not be used in cases where the mode of action has not been ascertained. 

An early theory linking the structure of polycyclic aromatic hydrocarbons with carcinogenesis is the K-region theory of Pullman and Pullman,197,198 according to which (1) carcinogenic activity in aromatic hydrocarbons is determined by the existence of an active K-region, and (2) if the molecule... 

M. Poulsen, D. Spangler, and G. H. Loew, Mol. Toxicol., 1, 35 (1987). Nitrosamine Carcinogen Activation Pathway Determined by Quantum Chemical Methods. 

In classical structure-activity studies, most of the attempts concentrated on correlating the activity with one of the molecular properties— e.g., the carcinogenic activity of polynuclear aromatic compounds with their electronic structure (18, 19), the narcotic activity with lipophilicity 20, 21), the insecticidal activity of cyclodienes with their three-dimensional molecular silhouette 22), etc. Sometimes the activity correlated well with only one of the molecuar parameters. In our approach these are special cases where other physicochemical properties do not play critical roles in determining the variation in the activity within a set of congeners so that the coefficients defining these other properties are zero. 

Initial work by Meselson and Russell has suggested that a fairly good correlation exists between the two potencies across a broad range of chemical classes. This initial study included only 14 chemicals, however, and it has been pointed out that the correlation between mutagenic and carcinogenic activities does not always hold within chemical classes such as the nitrosamines. It is clear that further work will be necessary to determine the extent of this type of correlation. Unfortunately, one of the principal difficulties in conducting this... 

The appearance of carcinogenic activity in aromatic hydrocarbons is determined by the existence of a K-region, whose complex index is equal to or smaller than 3.31 0. (These complex indices are defined by Pullman and Pullman (30) is expressed in terms of resonance integral... 

---