Characterization of the Photolysis of 2,4,5,2',4',5'-Hexabromobiphenyl

Characterization of the Photolysis of 2,4,5,2',4',5'-Hexabromobiphenyl.MILLIS, C. D., AND AUST, S. D. (1985). Fundam. Appl. Toxicol.5, 546–554. 2,4,5,2',4',5'-Hexabromobiphenyl (2,4,5-HBB)was irradiated with ultraviolet light in hexane with stirring,and photolysis was monitored by gas chromatography (GC). 2,4,5-HBBdecomposed at an average rate of 0.66±0.02 µmol/minand the reaction appeared zero order from 0.159 to 1.59 mM 2,4,5-HBB.Several polybrominated biphenyl (PBB) congeners were identifiedas photoproducts of 2,4,5-HBB. 2,4,5,2',5'-Pentabromobiphenyl(-PBB), formed by para debromination, accumulated at a higherrate than did 2,4,5,3',4'-PBB, formed by ortho debromination.2,4,5,2',4'-PBB was formed by meta debromination. 3,4,3',4'-Tetrabromobiphenyl(-TBB) was found as a secondary photoproduct, formed by orthodebromination of 2,4,5,3',4'-PBB. 2,5,2',5'-TBB and 2,4,2',5'-TBBwere formed by debromination of 2,4,5,2',5'-PBB para and meta,respectively. 2,5,3',4'-TBB could be formed by either orthodebromination of 2,4,5,2',5'-PBB or para debromination of 2,4,5,3',4'-PBB.Rates of degradation and accumulation of the penta- and tetrabrominatedbiphenyls were also studied. The ultraviolet spectra of the2,4,5-HBB photolysis mixture, as well as the purified components,were studied and are also reported     

Promotion of Altered Hepatic Foci by 2,3',4,4',5-Pentachlorobiphenyl in Sprague-Dawley Female Rats

The tumor promotion potential of 2,3',4,4',5-pentachlorobiphenyl(PCB-118) was studied in a two-stage initiation/promotion bioassayin female Sprague-Dawley rats. The animals were initiated byintraperitoneal administration of N-nitrosodiethylamine afterpartial hepatectomy. After 5 weeks of recovery, the promotionperiod commenced by once-weekly subcutaneous administrationsof PCB-118 at six dose levels (10, 40, 160, 640, 2500, and 10,000µg/kg body weight/week) for 20 weeks. In addition, threeof these dose levels (40, 640, and 10,000 µg/kg body weight/week)were administered for 52 weeks. Evaluation of hepatic foci positivefor glutathione S-transferase P demonstrated that the mono-orthochlorine substituted congener PCB-118 significantly increasedthe number of foci/cm³ of liver in the two highest dose groupsafter 20 weeks, but did not significantly increase the percentageof the liver occupied by foci. After 52 weeks of treatment,both the percentage and the number of foci/cm³ were significantlyincreased in the highest dose group. A toxic equivalency factorbased on foci development during 20 weeks of treatment wouldbe less than 0.00002. Altered relative liver and thymus weightswere observed after treatment with both substances as well asan induction of methyl cholanthrene- and phenobarbital-inducibleisoenzymes of cytochrome P450 monooxygenase. These results showthat PCB-118 has a potency to enhance foci growth in rat liver,although the potency is low compared to that of structurallyrelated compounds.     

Transport of 2,4,5,2',4',5'-hexachlorobiphenyl by lipoproteins in vivo

Lipoproteins are currently being recognized as transport vehicles for lipophilic drugs and xenobiotic chemicals in plasma. The weight of in vitro evidence suggests lipoproteins as the principal carries of 2,4,5, 2',4',5'-hexachlorobiphenyl (6-CB) in plasma from normolipidemic rats and humans. The present study examined the in vivo distribution of 6-CB among lipoproteins as well as the influence of time on the absolute amount and proportion of 6-CB associated with each density fraction. Plasma obtained between 1 min and 24 hr after an iv injection of 6-[14C]CB was separated into very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) fractions by sequential ultracentrifugation. The in vivo results corroborate the in vitro data which suggest LDL to be a major transport vehicle for 6-CB in plasma. However, the preference of 6-CB for LDL existed for only a short time following injection. From 6 to 24 hr after administration of 6-CB, there was a shift in the distribution of the PCB from LDL to HDL and the remaining protein-rich bottom fraction. By 24 hr, the proportion of 6-CB in LDL had declined from 80% of the plasma concentration to 30%, while that in HDL had doubled. Furthermore, the amount of 6-CB in the bottom fraction accounted for 35% of the radioactivity in plasma at 24 hr as opposed to less than 5% up to 1 hr after administration. The absolute contents of 6-CB in both HDL and the bottom fraction also increased during the later time points. Analysis of the decay curves of 6-CB among the various lipoproteins further substantiated a change in the distribution of 6-CB over time. The decay of 6-CB in LDL most closely resembled its disappearance from plasma. The content of 6-CB remaining in plasma at 24 hr was equally distributed among LDL, HDL, and the bottom fraction. Changes in lipoprotein composition during the 24-hr period could not explain 6-CB redistribution, since there were no significant differences in the proportion of constituents comprising VLDL, LDL, HDL, or the bottom fraction.     

Toxicity and Microsomal Enzyme Induction Effects of Several Polybrominated Biphenyls of Firemaster

Toxicity and Microsomal Enzyme Induction Effects of SeveralPolybrominated Biphenyls of Firemaster. Dannan, G.A., Sleight,S.D. and Aust, S.D. (1982). Fundam. Appl. Toxicol. 2:313-321.Some toxicological and pharmacological effects of 2,4,5,2',5'-penta-(congener 1), 2,3,4,2',4',5'-hexa- (congener 5), 2,4,5,3',4',5'-hexa-(congener 6), 2,3,4,5,3',4',-hexa- (congener 7), and 2,3,4,5,2',3',4'-hepta-bromobiphenyl(congener 9) were evaluated in male rats given a single 90 mg/kgip injection and killed seven days later. Only congener 7 depressedbody weight gain, spleen and thymus weights, and caused severehistopathological changes in the thymus. Congener 7 caused thelargest increase in liver weight and the most changes in liverpathology while congener 1 failed to enlarge this organ andcaused the mildest ultrastructural changes. Liver microsomeswere isolated and evaluated for enzyme induction from all treatedrats except those administered congener 6, which was previouslyidentified as a mixed-type enzyme inducer (Dannan et al. 1978b).All congeners increased the liver microsomal cytochrome P-450content, but only congener 7 shifted the carbon monoxide differencespectrum absorption maximum to 448.0 nm. The microsomal ethylisocyanide difference spectrum 455/430 nm ratio was increasedthe most by congener 7 (3 fold). All congeners increased cytochromeP-450 reductase and microsomal epoxide hydrase activities bynearly 1.5–3 fold. Congener 7 failed to induce amino-pyrine-N-demethylaseactivity but the remaining congeners increased it by 2 fold.Congener 7 was the most effective inducer of benzo[a]pyrenehydroxylase and p-nitrophenol UDP-glucuronyl transferase. Theseresults add to the suggestion that the presence of an orthohalogen on a polyhalo-genated biphenyl does not completely abolishtoxicity or 3-methylcholanthrene-type microsomal enzyme induction.     

Mechanisms for the Release and Redistribution of 2,4,5,2',4',5'-Hexachlorobiphenyl (6-CB) from Hepatic Tissues in the Rat

Mechanisms for the Release and Redistribution of 2,4,5,2',4',5'-Hexachlorobiphenyl(6-CB) from Hepatic Tissues in the Rat. RAU, L. A., AND VODICNIK,M. J. (1986). Fundam Appl. Toxicol. 7, 494-501. The translocationof 6-[¹⁴C]CB from rat hepatic tissues to various media was studiedemploying in situ hepatic perfusion and primary hepatocyte culturetechniques. 6-[¹⁴C]CB release from the hepatic tissues of femalerats pretreated with 2 µCi 6-CB was dependent on the relativeproportion of perfusate buffer components. Approximately 10%of hepatic 6-CB was released into buffer containing either 4%BSA or 4% BSA and 100 mg/dl exogenous human very low densitylipoproteins (VLDL). 6-CB release was significantly increasedunder simulated hyperhpidemic conditions (400 mg VLDL/dl). Releasedeclined when BSA was eliminated or replaced with Dextran. Thedistribution of 6-CB between the triacylglycerol (TG)-rich VLDLand the protein buffer components was found to be dependenton the ratio of TG:protein. Under hyperlipidemic perfusate conditions,approximately 83% of the 6-CB associated with the BSA fraction.Under normolipidemic conditions, 99% of the 6-CB associatedwith BSA. The concentration of 6-CB in TG was greatly increasedunder hyperlipidemic conditions. Thus, 6-CB distribution undersimulated normolipidemic conditions could not be explained bysaturation of the VLDL fraction. Approximately 15% of 6-CB wasreleased from hepatocytes prepared from late pregnant or age-matchedcontrol rats. Eighty percent of 6-CB was associated with VLDLsecreted from hepatocytes. The TG:protein ratio in culture mediawas approximately 1:6 while ratios of 1:20 or 1:600 occurredin the perfusion studies. These data suggest that 6-CB may bereleased from hepatic tissues in association with newly synthesizedTG, but that once in the circulation, its distribution is dependenton the ratio of TG to protein present.     

The disposition and elimination of two sequential doses of 2,4,5,2',4',5'-hexachlorobiphenyl

It has been suggested based on fecal elimination data that a second dose of 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) is eliminated more rapidly from male rats than a first dose of 6-CB due to a differential accumulation of the two 6-CB doses within individual adipocytes. This phenomenon was further examined and extended to assess tissue levels of the compound in male rats which received either 0.6 mg/kg unlabeled or 14C-6-CB iv (dose 1). Fourteen days later, those animals which had received unlabeled 6-CB were administered 0.6 mg/kg 14C-6-CB. One-half of those rats which had received 14C-6-CB as dose 1 were administered unlabeled 6-CB after 14 days, and the remainder did not receive a second dose. The fecal excretion of radiolabeled 6-CB from rats treated only with 14C-6-CB was 5.3% of the total dose from days 14 through 28 post-treatment. Those rats receiving 14C-6-CB followed by unlabeled 6-CB excreted 4.4% of the total radiolabeled dose. Animals treated with 14C-6-CB as the second dose excreted 9% of their total radiolabeled dose within 14 days of treatment and those receiving only 14C-6-CB excreted 11% over the same time interval. Urinary elimination of radioactivity was negligible in all treatment groups. The pattern of distribution of 14C-6-CB in tissues was similar among all treatment groups. These data suggest that a second dose of 6-CB is not distributed differently from the first in growing male rats.     

2,4,5,2',4',5'-Hexachlorobiphenyl: distribution, metabolism, and excretion in the dog and the monkey

The tissue distribution, metabolism, and excretion of 2,4,5,2′,4′,5′-hexachlorobiphenyl (2,4,5-HCB) were investigated in beagle dogs and cynomolgus monkeys (Macacca fascicularis). Following a single iv dose of [¹⁴C]2,4,5-HCB (0.6 mg/kg), excreta, blood, and tissues were collected at time intervals ranging from 30 min to 15 days for dogs and 2 hr to 90 days for monkeys. The concentration of 2,4,5-HCB and its metabolites was determined in all samples. Elimination of the parent PCB from the blood of both species was biphasic with a terminal phase elimination rate constant of 0.045 day^?1 for the dog and 0.015 day^?1 for the monkey. By 15 days the dog had excreted 66% of the dose, 63% in the feces, and 3% in the urine. The percentage dose remaining was found largely as parent compound in the adipose tissue (16%), skin (6%), and muscle (2%). By 90 days, the monkey had excreted only 18% of the dose (17% in feces, 1% in urine). Again, the major storage depots for nonexcreted dose were adipose tissue 945%) and skin (5%). In anesthetized dogs, 0.8% of the dose appeared in the bile within 2 hr, while only 0.2% of the dose appeared in the bile of anesthetized monkeys in 2 hr. The monkey excreted a greater percentage of dose as parent compound into the bile than the dog. The data provide evidence that the pharmacokinetic behavior of 2,4,5-HCB in the monkey is similar to that observed in other species. However, the dog is unique from other species in that it can readily eliminate 2,4,5-HCB.     

Comparative toxicity study of 2,4,5,2',4',5'-hexachlorobiphenyl and a polychlorinated biphenyl mixture in rabbits

Three groups of rabbits were treated daily (5 times per week for 28 days) with 120 mg 2,4,5,2′,4′,5′-hexachlorobiphenyl, 120 mg polychlorinated biphenyl (PCB) mixture (Aroclor 1260^®) and the solvent isopropanol, respectively. The dermal application resulted in early macroscopic skin lesions in the Aroclor group. The lesions in the 2,4,5,2′,4′,5′-hexachlorobiphenyl group appeared later on and were less severe. This difference was confirmed microscopically: hyperplasia and hyperkeratosis of the follicular and epidermal epithelium were more severe in the Aroclor^® group. Fecal coproporphyrin levels were significantly increased in the experimental groups. Enhanced liver weights were found in both test groups. Liver injury, as judged by light microscopic lesions and elevated serum transaminase levels, was somewhat more severe in the hexachlorobiphenyl group when compared with the Aroclor^® group, though the mean liver content was about the same (respectively, 239 and 236 ppm). Light microscopic findings included subcapsular necrosis, zonal necrosis, hydropic degeneration, as well as a peripheral and perinuclear shift of cell organelles, and focal cytoplasmic hyalin degeneration. In electron microscopy the shift was found to be due to a proliferation of smooth surfaced membranes of the endoplasmic reticulum (SER), resulting in a displacement of rough surfaced membranes (RER) and mitochondria. The hyalinized cytoplasm was recognized as tightly packed tubules of proliferated SER, that is considered as hypertrophic, hypoactive SER. The contribution of chlorinated dibenzofurans and pure PCB in the toxicity of crude PCB mixtures is discussed.     

Transfer of 2,4,5,2',4',5'-hexachlorobiphenyl across the in situ perfused guinea pig placenta

The transplacental crossover of 14C-2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) from the maternal circulation to the fetal side of the placenta was examined in intact fetuses and following the in situ perfusion of the guinea pig placenta. Fetal, late pregnant, and nonpregnant female guinea pig lipoprotein profiles and the association of 6-CB with these plasma constituents were also determined in vivo. Very low density lipoprotein (VLDL) concentrations were 10-fold higher in fetal than in maternal plasma, and the great majority of 6-CB which was transferred to intact fetuses became associated with this plasma fraction. 6-CB was found primarily in association with low density lipoproteins (LDL) in nonpregnant animals. In the late pregnant guinea pig, 6-CB became primarily associated with plasma protein in spite of circulating protein concentrations lower than those seen in the nonpregnant state. No differences in the levels of the three plasma lipoprotein classes were observed between pregnant and nonpregnant animals. It was found that an amount of 6-CB similar to that found in intact litter mates crossed the perfused placenta over the same time period. Despite the much higher VLDL concentrations on the fetal side of the placenta and the association of 6-CB with VLDL in intact fetuses, addition of 1,000 mg/dl VLDL to the 5.4% bovine serum albumin perfusion medium failed to influence the magnitude of 6-CB crossover. 6-CB crossover was influenced by protein concentration in the perfusion media in a concentration-dependent fashion. It is hypothesized that 6-CB and free fatty acids traverse the placenta and are retained by the fetus via similar mechanisms.     

Comparative adipose tissue kinetics of thiopental, DDE and 2,4,5,2',4',5'-hexachlorobiphenyl in the rat

A comparative study on the fate of thiopental, DDE, and 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) with emphasis on adipose tissue kinetics was carried out after single i.v. doses to adult male rats. The time course of the concn. in blood, adipose and other tissues were determined for the three compounds for periods up to 40 h, 14 and 28 d, respectively, allowing for mass balances and for calculation of pharmacokinetic parameters. Appreciable amounts of thiopental, DDE and 6-CB appeared in adipose tissues, but the kinetics were profoundly different, the adipose tissue concn. peaking after one hour, 17 h, and five to six weeks, respectively. Thus, although DDE and 6-CB are much more lipophilic than thiopental, they were very much slower in entering adipose tissue. The results indicate that adipose tissue storage of drugs and other xenobiotics cannot be explained as a simple partition phenomenon. Rather, disposition in adipose tissue may be determined by initial binding in other tissues.     

Incorporation of labeled 2,4,5,2',4',5'-hexachlorobiphenyl into the nuclear fraction of rat hepatocytes in vivo

2,4,5,2',4',5'-[14C] Hexachlorobiphenyl (2,4,5-HCB) a slowly metabolized PCB was given to rats by gastric incubation. The hepatocyte nuclei (HCN) were then isolated and treated with specific hydrolytic enzymes in order to separate the nucleic macromolecules, protein RNA and DNA. The results show that 2,4,5-HCB binds in vivo to hepatocyte nuclei. Liver nuclear proteins bind 70% of 2,4,5-HCB and 30% is found in the DNA fraction. No radioactivity was found in the nuclear RNA fraction at this experimental time (16 h).     

Age- and Sex-Related Changes in the Components of the Hepatic Microsomal Mixed Function Oxidase System in Sprague-Dawley Rats

1. A study of the sex- and age-(4 to 103 weeks) related changes in liver microsomal mixed-function oxidase components of Sprague-Dawley rats, showed that total cytochrome P-450 ranged from 12.0 to 34.0 nmol/g, peaking between weeks 26 and 39; males had higher levels than females at weeks 4 to 51. Cytochrome b₅ ranged from 5.0 to 15.0 nmol/g with inconsistent age- and sex-related differences.

2. NADPH: cytochrome C reductase ranged from 2.6 to 4.8 μmol/min per g, with maximal activity at week 39; males had greater activity at weeks 12 to 78. NADH: cytochrome C reductase ranged from 5.2 to 26.9 μmol/min per g, peaking between weeks 51 and 78; females had greater activity at weeks 12 to 51.

3. This age- and sex-related pattern of changes in these components is specific to the Sprague–Dawley strain. There are slight but significant differences between sexes only in rats less than 1 year old. There was no significant correlation between rates of p-nitroanisole or aniline metabolism and cytochrome P-450 concentrations.     

Toxicity of 3,4,5,3',4',5'-hexabrominated biphenyl and 3,4,3',4'-tetrabrominated biphenyl

Immature male rats were given a single equimolar dose (21.3 mumol/kg body wt) of 3,4,5,3',4',5'-hexabromobiphenyl (HBB) or 3,4,3',4'-tetrabromobiphenyl (TBB) and terminated at various times up to 14 days after treatment. Hepatic microsomal aryl hydrocarbon hydroxylase (AHH) activity for the TBB treatment group was maximal at Day 2 and then steadily decreased, whereas this activity was induced in 1 day and remained high for the HBB treatment group. Tissue concentrations of HBB appeared to be unchanged over time whereas tissue concentrations of TBB decreased in a biphasic manner. Rates of in vitro metabolism of TBB with hepatic microsomes from TBB-treated animals showed a similar time-course relationship to AHH induction. HBB caused moderate to severe hepatic changes while TBB-treated rats had only mild hepatic changes. The relative binding of TBB by the hepatic receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was about 10 times that of HBB. The results suggest that even though the receptor-binding affinities imply that TBB should be more toxic than HBB, it is less toxic than HBB because it is metabolized. Studies with the chlorinated analogs of TBB and HBB suggested that PCB behave similarly. These results also suggest that receptor binding and AHH induction do not accurately reflect toxicity for polyhalogenated aromatic hydrocarbons which are metabolized, presumably because continued occupation of the receptor and persistent induction of some enzyme activity are required for toxicity.     

Distribution and excretion of 2,4,5,2',4',5'-hexabromobiphenyl, the major component of Firemaster BP-6.

The intestinal absorption, distribution, and excretion of the major component of Firemaster BP-6,2,4,5,2',4',5'-hexabromobiphenyl, has been studied in the male rat. This polybrominated biphenyl was readily absorbed from the intestine, initially distributed throughout the body, and eventually stored primarily in the adipose tissue, was not subject to appreciable metabolism, and was excreted almost exclusively in the feces and at a very slow rate. Approximately 90% of an oral dose was absorbed from the intestine, and extrapolation of the rate of excretion to infinity indicates that less than 10% of the total dose would ever be excreted.     

Co-induction of cytochrome P-450 isozymes in rat liver by 2,4,5,2',4',5'-hexachlorobiphenyl or 3-methoxy-4-aminoazobenzene

A multitude of xenobiotics have been demonstrated to co-induce either cytochromes P-450c and P-450d or cytochromes P-450b and P-450e in rat hepatic microsomes. Recently, the compounds 2,4,5,2',4',5'-hexachlorobiphenyl (HCB) and 3-methoxy-4-aminoazobenzene (3-MeO-AAB) have been suggested as selective inducers of cytochrome P-450b (Eur. J. Biochem. 151:67 (1985)) and P-450d (Biochem. Biophys. Res. Commun. 133:1072 (1985)), respectively. Since the identification of inducers with such unique characteristics would have implications with regard to the mechanism of induction of all four isozymes, we have examined the induction of cytochromes P-450b and P-450e by HCB and cytochromes P-450c and P-450d by 3-MeO-AAB in liver microsomes from adult male rats. Immunoblot analysis with monoclonal antibodies directed against cytochromes P-450b and P-450e indicate that HCB induces both isozymic species at the three dosage levels examined (10, 90, and 180 mg/kg). Similarly, 3-MeO-AAB does not appear to represent a unique inducer. Immunoblots of hepatic microsomes from animals treated with three different dosage regimens of 3-MeO-AAB demonstrate that, even at the lowest dosage level (50 mg/kg), both cytochromes P-450c and P-450d are induced. Moreover, immunoinhibition of 7-ethoxyresorufin O-deethylase (EROD) activity by monospecific antibody against either cytochrome P-450c or P-450d confirms this result. 3-MeO-AAB increases this enzyme activity 10-fold; approximately one-third of this induced activity is inhibited with monospecific anti-P-450c, while two-thirds is inhibited with monospecific anti-P-450d. This study also demonstrates that hepatic EROD activity is not an accurate estimate of cytochrome P-450c content since the majority of this enzyme activity in control and 3-MeO-AAB-treated rats is inhibited with monospecific anti-P-450d but not with monospecific anti-P-450c.     

Toxicity Studies of Epichlorohydrin in Sprague-Dawley Rats

ABSTRACT

Adult male and female Sprague-Dawley rats received epichlorohydrin via gavage in distilled water for 10 consecutive days at dose levels of 3, 7, 19, and 46 mg/kg-day, and for 90 days at dose levels of 1, 5, and 25 mg/kg-day. Epichlorohydrin did not adversely effect mortality, but toxicity, at the higher doses, was evident by: 1) losses in body weight gain and organ weights, 2) reductions in food and water consumption, and 3) in the hematological and microscopic examinations in both study periods. Significant decreases in erythrocyte count, hemoglobin, and hematocrit levels were found in the high dose level in males after 10 and 90 days. Dose-related increases in kidney and liver weights were observed in both sexes at 25 mg/kg-day in the 90-day study and in various organs for both 19 and 46 mg/kg-day in the 10-day study.

Histopathological examination identified the forestomach as the primary target organ for both sexes and in both studies with significant dose-related increases in mucosal hyperplasia (acanthosis) and hyperkeratosis. Based on the data presented, a lowest observable adverse effect level (LOAEL) for oral exposure of Sprague-Dawley rats to epichlorohydrin is 3 mg/kg-day for 10 days and 1 mg/kg-day is suggested as the no observed adverse effect level (NOAEL) for a 90 day oral exposure. These conclusions were the same whether the lesions were analyzed for each sex individually or whether the data in each study was pooled.     

Determination of the binding of 2,4,5,2',4',5'-hexachlorobiphenyl by low density lipoprotein and bovine serum albumin

The mechanism of transport of polychlorinated biphenyls (PCBs) to and from peripheral cells is not known. Plasma proteins, which bind a variety of compounds including hydrophobic molecules, are most likely to be involved in PCB transport. In order to study the role of lipoproteins in the transport and distribution of PCBs to cells, an assessment of the nature and extent of the interaction and binding of PCBs to plasma proteins is necessary. In this report a simple filter assay procedure for the analysis of binding of 2,4,5,2',4',5'-hexachlorobiphenyl (HCB) by low density lipoproteins and serum albumin is described. The method allowed compete recovery of the PCBs, and reduced errors due to nonspecific binding to the apparatus to insignificant values. Low density lipoprotein bound HCB at several noninteractive sites (number of binding sites n = 30; binding constant K = 2.7 x 10(5); dissociation constant Kd = 7.2 x 10(-6) M). Bovine serum albumin bound HCB at one noninteractive site (n = 0.53; K = 5.1 x 10(5); Kd = 1.9 x 10(-6) M). The results indicate that albumin and low density lipoprotein bind HCB effectively and suggest that plasma proteins may play a role in its distribution to peripheral cells.     

The influence of time of maternal exposure to 2,4,5,2',4',5'-hexachlorobiphenyl on its accumulation in their nursing offspring

2,4,5,2',4',5'-Hexachlorobiphenyl (6-CB) is mobilized from rodent tissues during the lipid depletion associated with food restriction or lactation, the latter condition resulting in the substantial elimination of the maternal body burden of the chemical to nursing offspring. The present study was undertaken to determine whether the rate and/or magnitude of accumulation of 6-CB in nursing offspring differed with time following PCB administration to the maternal animal. Female ICR mice were administered two doses of 6-CB. Group I animals received [14C]-6-CB as weanlings (15-20 g) followed by unlabeled 6-CB 5 weeks later, after mating, on Day 1 of gestation. Group II received unlabeled 6-CB as weanlings and [14C]-6-CB on Day 1 of gestation. Thus, 14C identified the mobilization and elimination of either the first or the second dose of 6-CB in the treatment groups (I = [14C]-6-CB, 6-CB; II = 6-CB, [14C]-6-CB). Both groups of animals retained approximately 80% of the administered radiolabeled dose. The tissue distribution of [14C]-6-CB in group II as a percentage of the body burden was not different from that in group I as determined from maternal tissue concentrations on Day 14 of gestation. The percentage of the maternal body burden of [14C]-6-CB accumulated in suckling offspring of group II mothers was significantly greater than that in group I offspring on Day 1 (I, 2.2 +/- 0.5%; II, 3.5 +/- 0.4%), Day 3 (I, 14.8 +/- 1.9%; II, 24.6 +/- 2.7%), Day 5 (I, 16.8 +/- 1.4%; II, 24.8 +/- 0.8%), and Day 12 (I, 32.3 +/- 0.5%; II, 45.5 +/- 1.7%) postpartum. This differential elimination was reflected in the t1/2 of elimination of the radiolabeled dose from parametrial fat during lactation, which was significantly longer in group I (14 days) than group II maternal animals (9 days). The observations that the last dose of 6-CB administered was the first to be mobilized from the whole animal, and that this was reflected in 6-CB release from parametrial fat, suggest that this highly lipophilic chemical is not homogeneously distributed within storage depots.     

Toxicity Studies of 1,3-Dichlorobenzene in Sprague-Dawley Rats

ABSTRACT

Male and female Sprague-Dawley rats received 1,3-dichlorobenzene daily by corn oil gavage for 10 or 90 consecutive days. The 10-day study doses were 0, 37, 147, 368 and 735 mg/kg; the 90-day study doses were 0, 9, 37, 147 and 588 mg/kg. In the 10-day study, there was a significant depression of body weight in both sexes at 735 mg/kg. Liver weights were significantly increased in both sexes at 368 and 735 mg/kg. Serum cholesterol levels were significantly elevated in both sexes at 368 and 735 mg/kg. Histopathological evaluation revealed centrolobular hepatocellular degeneration at 368 mg/kg in males and 735 mg/kg in females.

In the 90-day study, body weights were significantly depressed in both sexes at 588 mg/kg. Normalization of food and water consumption by final body weight indicated that at 588 mg/kg both sexes had increased food and water consumption relative to controls. Absolute and relative liver weights were significantly increased in both sexes at 147 and 588 mg/kg. Relative kidney weights were significantly higher in both sexes at 588 mg/kg and in males at 147 mg/kg. Serum cholesterol and calcium levels were significantly elevated over controls in females at 37,147, and 588 mg/kg, and in males at all dose levels. Histopathological evaluation at 147 and/or 588 mg/kg demonstrated liver and thyroid lesions in both sexes, and pituitary and kidney lesions in males. A NOAEL was not firmly established.