Studies of dose distribution, premutagenic events and mutation frequenciesfor benzo[a]pyrene aiming at low dose cancer risk estimation

Cancer risk assessment of polycyclic aromatic hydrocarbons (PAH) is complic ated by several of these compounds exerting a promoter action leading to hi gh tumour incidences at high doses. Cancer risks at low doses corresponding to the uptake from air and food in the general environment would best be e stimated on the basis of measurement of in vivo target doses of genotoxic ( mutagenic) intermediates and a determination of mutation frequency per unit of dose. In experiments ultimately aiming at a risk assessment of environm ental PAH from in vivo doses benzo[a]pyrene (BaP) was chosen as a model. ga mma -Radiation has earlier been used as a reference standard in cancer risk estimation of genotoxic chemicals where dose equivalents (rad-equivalents) have been shown to give reliable risk estimates for several alkylating age nts. Variation in dose of BaP diolepoxide between organs was studied by mea surement of deoxyguanosine-N-2 adducts in DNA after administration of par b y gavage to mice of a strain with reduced DNA repair (Xpa(-/-)). The adduct levels in spleen, forestomach, stomach and small intestine were approximat ely the same; with the adduct level in spleen as reference it was twice as high in liver and lung and about half as high in colon tissue. A chemical o r radiation dose is proportional to the cumulative frequency of putatively premutagenic changes (premutagenic hits) in DNA, The mutation frequency per premutagenic hit (genotoxic chemicals) and per unit of dose (gamma -radiat ion) were calculated from acutely exposed V79 cells in order to determine t he mutagenic effectiveness of each agent. Based on the mutagenic effectiven ess determined in this study 10(-4) Gy can be regarded equally effective in causing phenotypically expressed HPRT mutations as the dose of BaP which c auses the formation of one deoxyguanosine-N-2 adduct per cell.