Covalent binding of styrene to DNA in rat and mouse.
Covalent binding of [7-3H]styrene (S) to DNA in vivo was measured and evaluated in a quantitative manner in order to investigate whether DNA adduct formation could form a mechanistic basis for tumor induction in a carcinogenicity bioassay. [7-3H]S was administered by inhalation in a closed chamber to male and female CD rats and B6C3F1 mice. After 4.5-6 h (rats) and 6-9 h (pools of four mice), S doses of 23-39 and 85-110 mg/kg respectively had been metabolized. DNA was purified to constant specific radioactivity which was measurable in all samples. DNA was enzymatically degraded to the 3'-nucleotides which were separated by HPLC for the detection of radiolabeled nucleotide-S adducts. The fractions with the normal nucleotides contained most of the radioactivity. In mouse liver DNA, a minute but significant level of adduct radioactivity was also detected. In the units of the Covalent Binding Index CBI = (mumol adduct/mol DNA nucleotide)/(mmol chemical/kg body wt), values of 0.05-0.09 and 0.07-0.18 were calculated for males and females respectively. In the rat, no DNA adducts were detectable in the liver at a limit of detection of 0.1 CBI units. Two of the four lung samples of the female rats showed adduct-related radioactivity corresponding to 0.07 CBI units. The CBI values are compatible with styrene 7,8-oxide as the reactive intermediate. The data are compared with CBI values and carcinogenic potencies of established genotoxic carcinogens. It is concluded that the DNA-binding potency of S is so low that significant tumor induction in a standard bioassay for carcinogenicity is unlikely to be due to DNA adduct formation alone. Consequences for a human risk estimation are discussed.
Cantoreggi
S
S
Institute of Toxicology, Swiss Federal Institute of Technology, Schwerzenbach.
Lutz
W K
WK
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity; D004247:DNA / Q000378:metabolism*; D005260:Female; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D012727:Sex Characteristics; D013045:Species Specificity; D020058:Styrene; D013343:Styrenes / Q000378:metabolism* / Q000633:toxicity
D002273:Carcinogens; D013343:Styrenes; D020058:Styrene; D004247:DNA