Relevance of different biological assays in assessing initiating and promoting properties of polycyclic aromatic hydrocarbons with respect to carcinogenic potency.
The results from assays that describe biological effects of polycyclic aromatic hydrocarbons (PAH) were explored using multivariate methods. Based on the availability of data, 29 PAH were included in the study. Five variables described the carcinogenic potency in rodents of the PAH. Biological effects were assayed using 14 variables. These included bacterial mutagenicity, enhancement and inhibition of bacterial mutagenicity, Ah receptor (AhR) affinity, and induction of enzymes that bioactivate many PAH to proximal bacterial mutagens. A principal components analysis (PCA) showed that the highest correlations with the cancer data were observed for variables describing AhR affinity, whereas bacterial mutagenicity data were poorly correlated with cancer data. When a partial least squares (PLS) regression analysis was applied, only one bacterial mutagenicity variable, but all AhR affinity variables were statistically relevant to describe carcinogenic potency. The latter variables were also correlated with the inhibition of bacterial mutagenicity of benzo[a]pyrene. It was concluded that structural requirements for AhR affinity are the same as those required for metabolism by enzymes that bioactivate benzo(a)pyrene. Negative correlations between mutagenicity and induction of enzymes were observed. The roles of cancer initiation and cancer promotion are discussed regarding the biological properties studied. It is proposed that bacterial mutagenicity reflects the cancer initiation potency, whereas the AhR affinity reflects the promotive effect of some PAH at the high doses applied in rodent carcinogenicity tests. It is thus indicated that initiation and promotion are provoked by different chemical species: reactive metabolites and the parent hydrocarbons, respectively. At doses reflecting a normal human exposure situation the effects of initiation may be more important in the course of chemical carcinogenesis. The mechanisms of cancer initiation and cancer promotion should therefore be studied in more detail for reliable quantitative risk assessments.
Sjögren
M
M
Department of Genetic and Cellular Toxicology, Wallenberg Laboratory, Stockholm University, Sweden.
Ehrenberg
L
L
Rannug
U
U
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D006801:Humans; D007256:Information Systems; D009152:Mutagenicity Tests; D009369:Neoplasms / Q000378:metabolism; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D012044:Regression Analysis; D012377:Rodentia / Q000378:metabolism; D013223:Statistics as Topic
D002273:Carcinogens; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2