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Tetrabromobisphenol A Bis(2,3-dibromopropyl) ether (TBBPA-BDBPE) is a high production volume brominated flame retardant (BFR) used in consumer products, resulting in ubiquitous human exposure. Although the major route of exposure for this chemical is believed to be via ingestion, dermal contact is likely via contaminated dust. Independent trials of a single dose of 100 nmol/cm(2) (~1 µCi [(14)C]/cm(2)) of [(14)C]-radiolabeled TBBPA-BDBPE was applied to whole rat skin (in vivo) or split-thickness human and rat skin (ex vivo) to estimate in vivo human percutaneous uptake. [(14)C]-radioactivity was quantified to determine dermal absorption (dose retained in dosed skin) and penetrance (dose recovered in receptor fluid [ex vivo] or tissues/excreta [in vivo]) over 24 h. In vivo absorption and penetration for rat skin was 26% and 1%, with a maximum flux of 44±9 pmol/cm(2)/h. In ex vivo rat skin, absorption and penetration and absorption values were 23% and 0.3% (flux = 26±8 pmol/cm(2)/h). In ex vivo human skin, 53% was absorbed and penetration was 0.2% with a maximal flux of 16±12 pmol/cm(2)/h. Computed maximal flux for in vivo human skin was 21±9 pmol/cm(2)/h with expected total absorption of ~80% and a penetration of

Tetrabromobisphenol A (TBBPA) is a brominated flame retardant used globally at high volumes, primarily in the epoxy resin of circuit boards. It has been detected in the environment and in humans. The National Toxicology Program found that chronic oral TBBPA treatment of 250 mg/kg and higher caused an increased incidence of uterine lesions in female Wistar Han rats. The present laboratory has previously reported changes in gene expression associated with estrogen homeostasis in liver and uterine tissue of adult female Wistar Han rats after five days of gavage with 250 mg/kg of TBBPA. Microarray analysis of tissue from these same TBBPA-treated rats was performed to detect additional pathways perturbed by TBBPA. Microarray analysis of uterine tissue detected downregulation of genes in pathways of the immune response following TBBPA treatment. These results, along with validation of associated gene expression changes using droplet digital PCR, are reported here. Our findings suggest mechanisms that may be related to estrogen-mediated immunosuppression.

Two groups of C57BL/6J mice received a single oral dose of 1 nmol/kg 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin (TCDD) alone or in combination with 300 mumol/kg 2,2',4,4',5,5'-hexachlorobiphenyl (HxCB). The disposition of TCDD in liver, fat, skin, spleen, lung and blood was studied at days 3, 7, 13 and 34 after dosage. HxCB cotreatment increased hepatic TCDD levels and, consequently, significant increases of the liver/fat distribution ratio were observed. HxCB cotreatment did not significantly affect TCDD levels in fat or other tissues. The elimination rates of TCDD were not influenced by HxCB cotreatment in any of the tissues. It is concluded that HxCB cotreatment alters the body distribution of TCDD in mice but does not influence the elimination rate of TCDD.

A physiologically based pharmacokinetic (PBPK) model was developed to describe the disposition of benzene in 3- and 18-month C57BL/6N mice and to examine the relevant physiologic and/or biochemical parameters governing previously observed age-related changes in the disposition of benzene. The model developed was based on that of Medinsky et al. (Toxicol. Appl. Pharmacol. 99 (1989) 193-206), with the inclusion of an additional rate constant for urinary elimination of benzene metabolites. Experimentally determined tissue partition coefficients for benzene in 3- and 18-month mice, as well as actual body weights and fat compartment volumes, were included as part of the model. Model simulations were conducted for oral exposure of 3-month mice to 10 and 200 mg benzene/kg and for oral exposure of 18-month mice to 10 and 150 mg benzene/kg. Total amount of benzene metabolized, as well as metabolism of benzene to specific metabolites and their elimination, was simulated. Modeling results for total amount of benzene metabolites eliminated in urine over a 24-h period at 10 mg/kg showed that a greater total amount of benzene metabolites would be excreted by 18-month versus 3-month old mice. At saturating doses of 150 and 200 mg/kg, total amount of benzene metabolites excreted 24 h post-dose was predicted to be equivalent in 18-month mice and 3-month old mice, but the rate of elimination over time was shown to be decreased in 18-month vs. 3-month mice. Decreased urinary elimination of total benzene metabolites was simulated by a smaller renal elimination rate constant in 18-month vs. 3-month mice, which is consistent with decreased renal blood flow noted in aging rodents. These model predictions were consistent with observed in vitro and in vivo experimental data. Model simulations for production of specific metabolites from benzene and elimination in urine agreed well with experimental data in showing no significant age-related changes in formation of benzene metabolites, with the exception of hydroquinone conjugates. Model simulations and experimental data showed decreased total urinary elimination of hydroquinone conjugates in 18-month vs. 3-month mice. The change in hydroquinone conjugate elimination with age was simulated in modeling experiments as an age-related increase in Km for production of hydroquinone conjugates from benzene. The results of this study indicate that age-related changes in physiology are primarily responsible for altered disposition of benzene in aged mice and suggest that concentrations for toxicity of benzene and/or metabolites may differ in target tissues of aged mice.

C57BL/6N mice, used to model induction of cleft palate and kidney malformations in offspring following maternal treatment with TCDD, were dosed on gestation day (gd) 9 with 2,2', 4,4', 5,5'-hexachlorobiphenyl (HCB) (62.5, 125, 250, 500, 1000 mg kg ) and/or gd 10 with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (15 or 18 μg kg ) to investigate the potential protective effects of HCB against TCDD-induced teratogenicity. Maternal body weight gain was increased by combinations of 15 μg TCDD kg and 125–500 mg HCB kg and decreased at doses of 15 μg TCDD kg + 1000 HCB mg kg . At the doses used in this study, there was no effect of either compound on number of live or dead offspring. Fetal body weight was slightly decreased in all groups dosed with ≥ 250 mg HCB kg . HCB did not induce cleft palate at a dose of 1000 mg kg , but did induce increases in hydronephrosis and hydroureter at 500 and 1000 mg kg . Combinations of HCB and TCDD decreased the incidence of cleft palate induced by TCDD alone, but only at doses of 15 μg TCDD kg combined with 125–500 mg HCB kg . The antagonism of hydronephrosis (incidence and severity) appeared over a narrower dose range (15 μg TCDD kg + 500 mg HCB kg ). HCB induced increases (3-fold) in ethoxyresorufin-O-deethylase (EROD) activity at doses of 500 and 1000 mg kg , suggesting that the limited antagonism of TCDD teratogenicity by HCB could be under the control of the Ah-receptor.

Laser Doppler velocimetry (LDV) is a non-invasive technique that measures capillary blood perfusion parameters (blood flow, volume and velocity) and can be used non-invasively to evaluate the effects of ageing on cutaneous blood perfusion. Male Fischer-344 rats (R) of 1, 2, 3, 8, 12, 16, 20 and 24 months and C57BL/6N mice (M) 1, 2, 3, 9, 15, 19 and 22 months (n = 6/mo) were used. Animals were anesthetized with ketamine/xylazine and LDV-measured blood flow was made on the backs of all animals. Five readings for each parameter were recorded in order to obtain a mean value of the individual. Skin biopsies (4 mm) were removed after LDV for assessing epidermal and dermal thickness and number of epidermal cell layers. The number of viable epidermal layers in M remained constant while in R it decreased with age. Epidermal thickness in both M and R decreased from 2-3 months and then remained constant. Dermal thickness decreased from 3 to 22 months in M, and increased in R from 1 to 2 months and remained constant. Blood flow of M increased between 1 and 2 months, remained constant to 19 months, then increased at 22 months; flow in R was constant except at 2 months. Thus age differences in epidermal and dermal thickness, and blood flow of M and R occur and should be considered when evaluating cutaneous toxicity studies in different-aged animals. These changes may potentially alter dermal absorption and/or distribution of xenobiotics.

Alteration of hormones has long been known to affect development. TCDD and related PHAHs modulate the levels of many hormonal systems. Dioxins cause a spectrum of morphological and functional developmental deficits. Fetotoxicity, thymic atrophy, and structural malformations are often noted. Delayed genitourinary tract effects have been observed, and recent studies reported behavioral effects. Highly exposed human offspring have exhibited developmental problems as well. Recently, hormonal and neurological abnormalities have been reported in infants from the general population. The complex alteration of multiple endocrine systems is likely associated with the spectrum of adverse developmental effects caused by dioxin and related compounds.

While the developmental toxicology of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its congeners has received considerable attention, the impact of advanced age on the biochemical effects and the pharmacokinetics of dioxins remains largely undetermined. In the present investigation, TCDD tissue distribution and cytochrome P4501A (CYP1A) induction were characterized in male C57BL/6N mice aged 10 weeks and 28 months at 7 days after administration of single oral [3H]TCDD doses ranging from 0.015 to 15 microgram/kg body wt. Determinations of hepatic marker enzyme activities for CYP1A1 (ethoxyresorufin O-deethylation, EROD) and 1A2 (acetanilide-4-hydroxylation, ACOH) indicated that the dose response curves for EROD induction by TCDD were nearly identical for the 2 age groups, but the ACOH induction response was greater in old mice. After receiving the 15 micrograms/kg dose, an increase (approximately 35%) in relative liver weight was observed 7 days after dosing in the 10-week mice, but not in the aged mice, and the hepatic concentration of TCDD was approximately 25% greater in young than old mice. No age difference was found in hepatic nuclear concentrations of TCDD. A dose-dependent increase in liver:fat tissue concentration ratios was noted at both ages, and adipose tissue and blood concentrations of TCDD did not vary significantly with age. In old mice however, TCDD concentrations in skin, kidney and muscle were all approximately twice those of young mice at the 15 micrograms/kg dose. These results suggest that advanced age may have differential effects on Ah receptor-mediated enzyme induction, while increased TCDD concentrations in certain tissues may have toxicological implications for older animals.

1,3-Butadiene, a colorless gas widely used as an intermediate in the production of synthetic rubber, is carcinogenic in rats and mice. Species differences exist in the sensitivity to inhaled 1,3-butadiene and the target tissue specificity for tumor formation. We examined whether repeated inhalation exposure of rats and mice to 1,3-butadiene would affect the rate of metabolism of 1,3-butadiene by lung and liver microsomes in these species. Male Sprague-Dawley rats and B6C3F1 mice were exposed nose-only to air (control) or 7600 +/- 170 ppm 1,3-butadiene (13,600 +/- 300 micrograms/l) and 740 +/- 10 ppm 1,3-butadiene (1300 +/- 20 micrograms/l), respectively, for 6 h/day for 5 days. After the last exposure, nasal tissue (rats only), lungs and livers were removed from the animals and microsomes were prepared. Microsomes from the different tissues were incubated with 6 mumol 1,3-butadiene and 10 mumol NADPH for 30 min and the rate of disappearance of 1,3-butadiene from the reaction flasks was quantitated. There was a statistically significant (P less than 0.05) depression in the rate of 1,3-butadiene metabolism (50%) in microsomes from lungs of both rats and mice that were exposed repeatedly to 1,3-butadiene compared to control animals. There was no effect of repeated 1,3-butadiene exposure on liver or nasal tissue (rats only) metabolism of 1,3-butadiene in rats or mice. The data from these studies indicate that it is unlikely that species differences in sensitivity or tissue susceptibility are due to an inductive or inhibitory effect of 1,3-butadiene on its own metabolism in the tissues examined.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TDCC) and 2,3,7,8-tetrachlorodibenzofuran (TCDF) cause the same spectrum of fetal anomalies in C57BL/6N mice. Pregnant dams were treated with TCDD, TCDF and combinations of the 2 compounds on gestation day 10, and examined for maternal and fetal effects on day 18. The fetal kidneys were the most sensitive target for teratogenicity. The dose response for cleft palate induction fit the probit model for both compounds, suggesting that TCDD was approximately 30 times more potent than TCDF. The interaction between these 2 compounds was consistent with a model for additive toxicity.

The effects of age on intestinal absorption of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied using adult male Fischer-344 rats of 3 different age groups: 13 weeks old (young), 13 months old (mature), and 26 months old (senescent). Absorption was measured with an in situ intestinal recirculation perfusion procedure. Absorption expressed in terms of ng TCDD absorbed/g intestinal dry weight/h was 166, 149 and 143 ng/g/h in the young, mature and senescent groups, respectively. When absorption was calculated in terms of ng TCDD absorbed/g mucosal dry weight/h, the decrease between the senescent rats and the 2 younger age groups, from 544 ng/g/h (young) to 351 ng/g/h (senescent), was not statistically significant (P less than 0.05). It was demonstrated that absorption of TCDD was unaffected by the presence of 2,4,5,2',4',5'-hexachlorobiphenyl (HCB) in the perfusate, but that HCB absorption was (P less than 0.01) enhanced by the presence of TCDD.

2,3-Dichloropropene (2,3-DCP), a component of commercial fumigants and nematocides, was mixed with [14C]2,3-DCP and given to rats by peroral (p.o.) or intraperitoneal (i.p.) administration. Urine, feces, and expired air were collected over 72 h. Excretion of radioactivity in urine predominated over other routes, with 66% to 75% of the dose excreted in 72 h. Feces contained from 13% to 21% of dose. 8% of the dose was exhaled as 14CO2. At the end of 72 h, only 2% to 3% of the dose remained in the carcass with the highest concentrations of 14C in liver, kidney, testes, and lung. Approx. 91% of the p.o. dose was absorbed from the gastrointestinal (GI) tract.

The dermal absorption of 14C-labeled 4,4'-thiobis(6-tert-butyl-m-cresol) (TBBC) was studied in female Sencar mice and male Fischer rats. Dermal application resulted in about 20% absorption in mice with more than 70% of the initial body burden (1BB) remaining on the treated skin site 3 days after treatment. In rats, less than 2% of a dermal dose was absorbed. This is in agreement with previous in vitro percutaneous absorption studies which have demonstrated that mouse skin is more permeable than rat skin to certain chemicals. Absorption did not increase linearly as the dose increased. Oral and i.v. exposures were conducted in the Sencar mice and compared to previously published rat oral and i.v. data. The disposition was similar between rats and mice after these routes of exposures, and the major route of elimination of absorbed TBBC was the feces in both species.