1. The excretion in the bile and urine after intravenous injection of 16 organic anions having molecular weights between 355 and 752 was studied in female rats, guinea pigs and rabbits. 2. These compounds were mostly excreted unchanged, except for three of them, which were metabolized to a slight extent (<7% of dose). 3. The rat excreted all the compounds extensively (22–90% of dose) in the bile. 4. In guinea pigs four of the compounds with mol.wt. 355–403 were excreted in the bile to the extent of 7–16% of the dose, four with mol.wt. 407–465 to the extent of 25–44% and eight compounds with mol.wt. 479–752 to the extent of 44–100%. 5. In rabbits four compounds with mol.wt. 355–465 were excreted in the bile to the extent of 1–8% of the dose, two compounds with mol.wt. 479 and 495 to the extent of 24 and 22%, and six compounds with mol.wt. 505–752 to the extent of 31–94%. 6. These results, together with those of other investigations from this laboratory, are discussed and the conclusion is reached that there is a threshold molecular weight for appreciable biliary excretion (i.e. more than 10% of dose) of anions, which varies with species: about 325±50 for the rat, 400±50 for the guinea pig and 475±50 for the rabbit. 7. Anions with molecular weights greater than about 500 are extensively excreted in the bile of all three species. 8. That proportion of the dose of these compounds which is not excreted in the bile is excreted in the urine, and in the three species, bile and urine are complementary excretory pathways, urinary excretion being greatest for the compounds of lowest molecular weight and tending to decrease with increasing molecular weight. 9. Some implications of this interspecies variation in the molecular-weight requirement for extensive biliary excretion are discussed.

1. The urinary and biliary excretion in the rat of 30 aromatic compounds with mol. wt. of 100-850, and largely excreted unchanged, has been studied. 2. These compounds fall into three groups as regards their pattern of elimination, which is related to mol. wt: group 1, with mol. wt. less than 350 and the major route of elimination the urine. When urinary excretion is prevented by ligating the renal pedicles the biliary excretion remains low. group 2, with mol, wt. of 450-850 which are excreted predominantly in bile. Even when the bile duct is obstructed, only small amounts of these compounds are found in urine. group 3, with mol. wt. of 350-450, which are eliminated extensively in both urine and bile. When one of these routes is blocked excretion by the other increases. 3. These studies emphasize the interrelationship of urine and bile as excretory routes for organic compounds. Urine and bile are complementary pathways; the extent of urinary excretion is greatest for the compounds of lowest mol. wt. and tends to decrease as mol. wt. increases and biliary excretion becomes more extensive.

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3-Hydroxy-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (3-OH-BP-7,8-diol) was isolated from arylsulfatase/beta-glucuronidase-treated bile of rats to which 3-hydroxybenzo[a]pyrene (3-OH-BP) has been administered. This triol was investigated for mutagenicity in Salmonella typhimurium (reversion to histidine prototrophy of strains TA 97, TA 98, TA 100 and TA 1537) and in V79 Chinese hamster cells (acquisition of resistance to 6-thioguanine). When no exogenous metabolizing system was added the triol was inactive, while 3-OH-BP showed weak mutagenic effects with all four bacterial strains. In the presence of NADPH-fortified postmitochondrial supernatant fraction (S9 mix) of liver homogenate from Aroclor 1254-treated rats, the mutagenicity of 3-OH-BP was potentiated, and the triol was activated to a mutagen(s). In the presence of S9 mix, the triol was 5-18 times more mutagenic than 3-OH-BP in strains TA 97, TA 100 and TA 1537, but both compounds showed similar mutagenic potencies with strain TA 98. These strain differences strongly suggest that the mutagenicity of 3-OH-BP in the S9 mix-mediated test was not exclusively due to metabolites of 3-OH-BP-7,8-diol. Trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol), like the triol, showed mutagenic effects only in the presence of S9 mix. Strain TA 1537 was reverted by the triol but not by the diol. In the other bacterial strains the diol was more mutagenic than the triol, the difference in potency being largest in strain TA 100 (2.5- to 10-fold, depending on the experimental conditions). In V79 cells, the diol was a potent mutagen, while the triol showed only very weak mutagenic effects. However the triol was more cytotoxic than the diol. High cytotoxicity of the triol was observed even in the absence of S9 mix. The results of the present study demonstrate that metabolites of 3-OH-BP-7,8-diol are biologically-active derivatives of benzo[a]pyrene. Comparison of the mutagenic effectiveness in different bacterial strains also reveals that metabolites of 3-OH-BP-7,8-diol and of BP-7,8-diol substantially differ in the kind of genetic alterations they evoke.