A 28-day oral dose toxicity study enhanced to detect endocrine effects of a purified technical pentabromodiphenyl ether (pentaBDE) mixture in Wistar rats

A 28-day subacute oral toxicity study was performed in Wistar rats with a purified preparation of the commercial pentabromodiphenyl ether (pentaBDE), DE-71. The applied OECD407 protocol was enhanced for endocrine and immune parameters, and to enable benchmark dose analysis. A vehicle control group and 7 dose groups were included, which received 0.27, 0.82, 2.47, 7.4, 22.2, 66.7 or 200 mg pentaBDE/kg bw/d (mkd). The liver appeared to be a key target organ, showing a marked increase of weight and centrilobular hepatocellular hypertrophy, probably due to the observed induction of P450 enzymes, notably CYP1A and CYP2B. A marked decrease of circulating total thyroxine (TT4) and an increase of plasma cholesterol were probably secondary to the liver effects. Furthermore, dose-dependently decreased weight of epididymis, seminal vesicles, and prostate, as well as sperm head deformities in males, and induction of CYP17 activity in adrenals in females were observed, all possibly related to anti-androgenic activity. Finally, we observed a substantial increase of large unstained cells in the blood and a decrease of apolar retinoids in the liver. All these effects had benchmark doses at the lower confidence bound (BMDL) in the low- or mid-dose range, but particular sensitive, potentially adverse effects were TT4 decrease (BMDLs 1.1 in males and 1.8 mkd in females), and decrease of hepatic apolar retinoids (BMDLs 0.5 mkd in males and 2.3 mkd in females). These results contribute to refinement of the hazard identification of pentaBDE and improved risk assessment of human exposure to this industrial chemical and environmental pollutant.     

Endocrine effects of hexabromocyclododecane (HBCD) in a one-generation reproduction study in Wistar rats

The brominated flame retardant (BFR) hexabromocyclododecane was tested in a one-generation reproduction assay in Wistar rats, enhanced for endocrine parameters. A solution of the compound in corn oil was mixed in the feed, targeting at dietary exposure of 0–0.1–0.3–1–3–10–30–100 mg/kg body weight/day (mkd) in parental rats during 10 (males) or 2 (females) weeks premating, during gestation and lactation, and in their F1 offspring from weaning until final necropsy. Effects were assessed in F1 animals. Livers of these animals showed increased HBCD concentrations, in a dose-dependent way. The trabecular bone mineral density of the tibia was dose-dependently decreased in females (BenchMark Dose Lower confidence bound, BMDL = 0.056 mkd). The IgG response after immunization with sheep red blood cells (SRBC) was increased in males (BMDL = 0.46 mkd). Further sensitive effects were decreased weight of the testis (BMDL = 1.5 mkd), increased fraction of neutrophilic granulocytes (BMDL = 7.7 mkd), decreased concentration of apolar retinoids in female livers (BMDL = 1.3 mkd), and decreased plasma alkaline phosphatase in females (BMDL = 8.6 mkd). CYP19/aromatase activity in the ovary was correlated to the concentration of γ-HBCD in the liver. A developmental origin of these effects is considered, and this is also true for sensitive effects observed in neurobehavioural testing in littermates from the same experiment, i.e. in the brainstem auditory evoked potentials and in a catalepsy test [Lilienthal, H., Van der Ven, L.T.M., Piersma, A.H., Vos, J.G. Neurobehavioral effects of the brominated flame retardant hexabromocyclododecane (HBCD) in rats after pre- and postnatal exposure, in press]. The low BMDLs of these effects may raise concern for human health, particularly when based on body burdens of HBCD, which leads to critical margins of exposure particularly for the occupational setting.     

A 28-day oral dose toxicity study enhanced to detect endocrine effects of hexabromocyclododecane in Wistar rats.

A 28-day repeated dose study in rats (OECD407) enhanced for endocrine and immune parameters was performed with hexabromocyclododecane (HBCD). Rats were exposed by daily gavage to HBCD dissolved in corn oil in 8 dose groups with doses ranging between 0 and 200 mg/kg bw per day (mkd). Evaluation consisted of dose-response analysis with calculation of a benchmark dose at the lower 95% one-sided confidence bound (BMDL) at predefined critical effect sizes (CESs) of 10-20%. The most remarkable findings were dose-related effects on the thyroid hormone axis, that is, decreased total thyroxin (TT4, BMDL 55.5 mkd at CES--10%), increased pituitary weight (29 mkd at 10%) and increased immunostaining of TSH in the pituitary, increased thyroid weight (1.6 mkd at 10%), and thyroid follicle cell activation. These effects were restricted to females. Female rats also showed increased absolute liver weights (22.9 mkd at 20%) and induction of T4-glucuronyl transferase (4.1 mkd at 10%), suggesting that aberrant metabolization of T4 triggers feedback activation of the thyroid hormone system. These effects were accompanied by possibly secondary effects, including increased cholesterol (7.4 mkd at 10%), increased tibial bone mineral density (> 49 mkd at 10%), both in females, and decreased splenocyte counts (0.3-6.3 mkd at 20%; only evaluated in males). Overall, female rats appeared to be more sensitive to HBCD than male rats, and an overall BMDL is proposed at 1.6 mkd, based on a 10% increase of the thyroid weight, which was the most sensitive parameter in the sequence of events.     

Distribution of bisphenol A and tetrabromobisphenol A in quail eggs, embryos and laying birds and studies on reproduction variables in adults following in ovo exposure

In a previous study, we showed that bisphenol A (BPA) had oestrogen-like effects in bird embryos, causing malformations of the oviducts in Japanese quail (Coturnix japonica) and feminisation of the left testis in chicken (Gallus domesticus). In this study, uptake and distribution of BPA and tetrabromobisphenol A (TBBPA) in embryos and laying quail were examined as well as variables related to reproduction in adult quail following administration of the compounds into the yolk of embryonated eggs. The uptake of radiolabelled BPA, TBBPA and the reference compound diethylstilboestrol (DES) was studied in the embryos using beta-spectrometry. Autoradiography was employed to examine distribution in egg and embryo after yolk sac injection of BPA or TBBPA and in laying birds, following intravenous and oral administration. Following embryonic exposure to BPA or TBBPA, sexually mature male birds were examined for reproductive behaviour and testis morphology, and females were examined for egg laying and oviduct morphology. Neither BPA (200 microg/g egg) nor TBBPA (15 microg/g egg) caused any significant oestrogen-like effects on the variables studied, although effects on the female oviducts after BPA exposure were indicated. Embryonic exposure to DES is known to cause profound effects on male sexual behaviour and female oviduct morphology at doses 3-5 orders of magnitude lower than the BPA and TBBPA doses used in the present study. The proportions of BPA and TBBPA taken up by the embryos after yolk sac injection were similar to the proportion of DES taken up. Differences in bioavailability, therefore do not account for any major part of the potency differences between DES and the two bisphenol A compounds. The concentration of radioactivity in the embryo, as revealed by autoradiography, was low compared with that in the yolk at all stages studied (days 6, 10 and 15). Pronounced labelling of the bile and the allantoic fluid was observed, however, indicating that both compounds were readily metabolised and excreted. Radiolabelled BPA and TBBPA administered to laying quail were largely excreted via the bile and 9 days after oral dosing, only small amounts of the labelled compound remained within the body. Maternal transfer of labelled BPA and TBBPA to the egg was low.     

Exposure to tetrabromobisphenol A (TBBPA) in Wistar rats: neurobehavioral effects in offspring from a one-generation reproduction study

Within the framework of an EU project on risk assessment of brominated flame retardants, TBBPA was studied for neurobehavioral effects in rats. To permit benchmark dose analysis, eight dose levels were chosen ranging from 0 to 3000mg/kg body weight. Exposure of parental rats started 10 and 2 weeks before mating in males and females, respectively, and was continued throughout mating, gestation and lactation. After weaning, exposure was continued in the offspring throughout life. Previous studies had indicated TBBPA-induced effects on thyroid hormones. Because of the known implication of thyroid hormones in neurodevelopment, the present experiments tested if TBBPA exposure affects thyroid-dependent neurobehavioral functions in offspring, such as auditory responses and conditioned fear. Sweet preference was included because of sex-specific effects in littermates. No statistically significant effects were found on context or cue conditioned fear or sweet preference. Auditory responses were examined with brainstem auditory evoked potentials (BAEPs) at approximately 50-110 days of age. BAEP thresholds and wave IV latency were increased in exposed female rats in the low frequency range. In male rats, thresholds were unaffected, but absolute latency of wave IV and interpeak latencies II-IV showed exposure-related increases at low frequencies. The outcome pattern suggests a predominant cochlear effect of TBBPA in females while in males neural effects are more apparent. According to benchmark analysis, the critical effect doses (CED) for prolongations of wave IV latency at 0.5kHz were in the range of 35-70mg/kg body weight with lower bounds (BMDL) of approximately 8mg/kg in males and females. The BMDL values for elevation of hearing thresholds in females were in the range of 1-40mg/kg body weight, depending on frequency. The benchmark doses for effects on the BAEP were similar to values for decreases in circulating thyroid hormones. The comparison of the exposure level at which the most sensitive effect was found with current human exposure levels yielded a margin of exposure of about 5, according to a recent risk assessment. Further investigations are needed to examine exposure pathways, fate in the body and effects of TBBPA.     

The utility of a rodent model in detecting pediatric drug-induced nephrotoxicity.

A multi-age rat model was used to identify potential age-related differences in renal injury following exposure to gentamicin (GM). In this study, 10-, 25-, 40-, and 80-day-old Sprague-Dawley rats were dosed with GM at 0, 50, or 100 mg kg(-1) body weight per day (mkd) sc for 6 or 14 days. Urine samples were collected up to 72 h after initial dosing. The maximum tolerated dose was lower in 10-day-old rats than for other ages (none survived 11 days of treatment). Eighty-day-old rats given the highest dose showed a diminished rate of growth and an increase in serum creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (Kim-1), and renal pathology. Ten- and 40-day-old rats given 100 mkd of GM for 6- or 14 days also had increased levels of serum BUN and Cr and renal pathology, whereas only mild renal alterations were found in 25-day-old rats. After 6 days of treatment with 100 mkd GM, significant increases in Havcr-1 (Kim-1) gene expression were detected only in 10- and 80-day-old rats. In urine samples, nuclear magnetic resonance and ultra performance liquid chromatography/mass spectrometry analysis detected changes related to GM efficacy (e.g., hippurate) and increases in metabolites related to antioxidant activity, which was greatest in the 80-day-old rats. The magnitude of the genomic, metabonomic, and serum chemistry changes appeared to correlate with the degree of nephropathy. These findings indicate that an experimental animal model that includes several developmental stages can detect age-related differences in drug-induced organ toxicities and may be a useful predictor of pediatric drug safety in preclinical studies.     

Subacute toxicity assessment of diflubenzuron,an insect growth regulator,in adult male rats

Diflubenzuron (DFB), an insecticide and acaricide insect growth regulator, can be used in agriculture against insect predators and in public health programs, to control insects and vectors, mainly Aedes aegypti larvae. Due to the lack of toxicological assessments of this compound, the objective of the present study was to evaluate the toxicological effects of subacute exposure to the DFB insecticide in adult male rats. Adult male rats were exposed (gavage) to 0, 2, 4, or 8 mg/kg of DFB for 28 days. No clinical signs of toxicity were observed in the DFB‐treated animals of the experimental groups. However, there was an increase in serum levels of alanine aminotransferase in the group that received 8 mg/kg/DFB/day and urea at doses of 4 and 8 mg/kg/DFB/day, without altering other biochemical or hematological parameters. The subacute exposure to the lowest dose of DFB caused significant decrease in testis weight, daily sperm production, and in number of sperm in the epididymis in relation to the control group. However, no alterations were observed in the sperm morphology, testicular, epididymis, liver and kidney histology, or testosterone levels. These findings unveiled the hazardous effects of DFB on male reproduction after the subacute exposure and special attention should be addressed to the effects of low doses of this pesticide. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 407–414, 2016.     

Neurobehavioral effects of tetrabromobisphenol A,a brominated flame retardant,in mice

Tetrabromobisphenol A (TBBPA) is widely used as a flame retardant and is suspected to be stable in the environment with possible widespread human exposures. In the present study, we investigated the behavioral effects of TBBPA and measured the levels of TBBPA in the brain after oral administration in mice. Acute treatment with TBBPA (5 mg/kg body weight) 3 h before the open-field test induced an increase in the horizontal movement activities. In contextual fear conditioning paradigm, mice treated with TBBPA (0.1 mg/kg or 5 mg/kg body weight) showed more freezing behavior than vehicle-treated mice. In addition, TBBPA (0.1 mg/kg body weight) significantly increased the spontaneous alternation behavior in the Y-maze test. The levels of TBBPA in the brain following TBBPA treatment were determined by using LC/ESI-MS/MS system. In the brain regions examined, high amounts of TBBPA were detected in the striatum after treatment with 0.1 mg/kg or 5 mg/kg body weight TBBPA, whereas non-specific accumulation of TBBPA in the brain was found after treatment with 250 mg/kg body weight TBBPA. These results suggest that TBBPA accumulates in brain regions including the striatum and induces the behavioral alterations. Together, the possibility of widespread human exposure to TBBPA warrants further studies to characterize its neurotoxicity.     

Effect of air pre-exposure on Tetrabromobisphenol A resistance in the clam Ruditapes philippinarum

The present study was conducted to evaluate how air pre-exposure influences the responses in gills and digestive gland of Ruditapes philippinarum on subsequent Tetrabromobisphenol A (TBBPA) exposure. Firstly, clams were maintained in seawater or pre-exposed to air for 24 h, and then exposed to 0 or 100 μg/L TBBPA. Clam tissues were sampled after 1 day (T1) and 7 days (T7) of exposure to TBBPA. The results showed that in comparison with TBBPA exposure alone, air pre-exposure following TBBPA exposure reduced TBBPA accumulation in both tissues, up-regulated mRNA levels of CAT, Hsp70 and pi-GST in gills, and induced GST activity and P-glycoprotein (Pgp) mRNA level in digestive gland of clams at T1, whereas increased lipid peroxidation at T7. Overall, the findings indicate that 24-h exposure to air can activate a priming mechanism withstanding the subsequent TBBPA exposure, which is transient and may change after prolonged subsequent exposure.     

Biotransformation and cytotoxicity of a brominated flame retardant, tetrabromobisphenol A, and its analogues in rat hepatocytes

The metabolism and cytotoxic effects of tetrabromobisphenol A (TBBPA), a phenolic flame retardant, and its analogues were studied in freshly isolated rat hepatocytes and isolated hepatic mitochondria, respectively. The exposure of hepatocytes to TBBPA caused not only concentration (0.25-1.0 mM)- and time- (0-3 h) dependent cell death accompanied by the loss of cellular ATP, adenine nucleotide pools, reduced glutathione, and protein thiols, but also the accumulation of oxidized glutathione and malondialdehyde, indicating lipid peroxidation. TBBPA at a weakly toxic level (0.25 mM) was metabolized to monoglucuronide and monosulfate conjugates: the amounts of glucuronide rather than sulfate conjugate predominantly increased, accompanied by a loss of the parent compound, with time. In comparative effects based on cell viability, mitochondrial membrane potential and some toxic parameters, bisphenol A (BPA) was less toxic than TBBPA and tetrachlorobisphenol A (TCBPA), which are not significant differences in these parameters. In mitochondria isolated from rat liver, TBBPA and TCBPA caused an increase in the rate of State 4 oxygen consumption in the presence of succinate, indicating an uncoupling effect and a decrease in the rate of State 3 oxygen consumption in a concentration-dependent manner (5-25 microM). Taken collectively, our results indicate that (i) mitochondria are target organelles for TBBPA, which elicits cytotoxicity through mitochondrial dysfunction related to oxidative phosphorylation at an early stage and subsequently lipid peroxidation at a later stage; and (ii) the toxicity of TBBPA and TCBPA is greater than that of BPA, suggesting the participation of halogen atoms such as bromine and chlorine in the toxicity.     

Subacute toxicity study of the combination of ginseng (Panax ginseng) and ashwagandha (Withania somnifera) in rats: a safety assessment

Ginseng (Panax ginseng) and Ashwagandha (Withania somnifera) are widely used as geriatric tonics. Both individually have not shown any toxicity on long term administration. Study was planned to assess the safety of the combination by doing subacute toxicity study in rats with 90 days oral administration using three doses. Food consumption, body weight, haematological, biochemical and histopathological parameters were studied. There was significant increase in body weight, food consumption and liver weight, and improved hematopoiesis was observed. Brain, heart, lung, liver, spleen, kidneys, stomach, testis and ovaries were normal on gross examination and histopathologically. Subacute toxicity studies in rats did not reveal any toxicity.     

An integrative cellular metabolomic study reveals downregulated tricarboxylic acid cycle and potential biomarkers induced by tetrabromobisphenol A in human lung A549 cells

Tetrabromobisphenol A (TBBPA) is extensively utilized as a brominated flame retardant in numerous chemical products. As an environmental contaminant, the potential human toxicity of TBBPA has been attracting increasing attention. Nonetheless, the exact underlying mechanisms of toxicological effects caused by TBBPA remain uncertain. In this study, we investigated the potential mechanisms of TBBPA toxicity in vitro in the A549 cell line, one of the widely used type II pulmonary epithelial cell models in toxicology research. Cell viability was determined after treatment with varying concentrations of TBBPA. Liquid chromatography–mass spectrometry (LC–MS) metabolomics and metabolic flux approaches were utilized to evaluate metabolite and tricarboxylic acid (TCA) cycle oxidative flux changes. Our findings demonstrated that TBBPA significantly reduced the viability of cells and attenuated mitochondrial respiration in A549 cells. Additionally, LC–MS data showed significant reductions in TCA cycle metabolites including citrate, malate, fumarate, and alpha-ketoglutarate in 50 μM TBBPA-treated A549 cells. Metabolic flux analysis indicated reduced oxidative capacity in mitochondrial metabolism following TBBPA exposure. Moreover, diverse metabolic pathways, particularly alanine, aspartate, and glutamate metabolism and the TCA cycle, were found to be dysregulated. In total, 12 metabolites were significantly changed (p < .05) in response to 50 μM TBBPA exposure. Our results provide potential biomarkers of TBBPA toxicity in A549 cells and help elucidate the molecular mechanisms of pulmonary toxicity induced by TBBPA exposure.     

Ethylene Glycol Monomethyl Ether II. Reproductive and Dominant Lethal Studies in Rats

Ethylene Glycol Monomethyl Ether II. Reproductive and DominantLethal Studies in Rats. Rao, K.S., Cobel-Geard, S.R., Young,J.T., Hanley, T.R. Jr., Hayes, W.C., John, J.A. and Miller,R.R. (1983). Fundam. Appl Toxicol. 3:80-85. Groups of male andfemale Sprague-Dawley (CD) rats were exposed to 0, 30, 100,or 300 ppm ethylene glycol monomethyl ether (EGME) vapor 6 hours/day,5 days/week for 13 weeks. The 0 and 30 ppm groups each contained30 rats/sex and the 100 and 300 ppm groups each had 20 rats/sex.Following the exposure period, males were bred to unexposedfemales to evaluate reproductive capability and dominant lethality.Additional matings of control and 300 ppm exposed males wereperformed during the post-exposure period in order to evaluatethe recovery of fertility. Exposed females were bred with unexposedmales to assess reproductive parameters. Results of the presentstudy indicate a potential for inhaled EGME to completely suppressfertility in male rats at the 300 ppm level. Fertility of theserats was partially restored at 13 weeks post-exposure. Bodyweights of animals in the 300 ppm group were reduced as a resultof the exposures. No dominant lethal effect or impaired fertilitywas observed in male rats exposed to 30 or 100 ppm EGME. Treatment-relatedpathologic alterations were observed only in male rats at the300 ppm level and included decreased testicular size and atrophicseminiferous tubules. Female rats tolerated up to 300 ppm EGMEwithout any adverse reproductive effects. Based on these results,it was concluded that the no-adverse effect level of EGME forfertility and reproduction was 100 ppm in rats.     

Effect of tetrabrombisphenol A on induction of apoptosis in the testes and changes in expression of selected testicular genes in CD1 mice

Tetrabromobisphenol A (TBBPA) is a substance widely used in industry as a flame retardant. TBBPA was found in the environment and was detected even in the human body. The effect of this chemical was observed in different cell lines in vitro and it is supposed that TBBPA may affect various hormonal systems in vivo. In this study we examined the effect of TBBPA on the reproductive parameters of two generations of outbred mice in vivo. Experimental and control animals of F1 generation were bred in various conditions to enable evaluation of the possible trans-generational effect. An increased incidence of apoptosis in the testes and changes in the morphometry of seminiferous tubules was detected in the experimental animals. In addition, changes in the expression pattern of selected genes encoding proteins that play an important role during spermatogenesis were observed. In contrast, sperm quality and reproduction were not affected by TBBPA.     

Reproduction Study of Dimethylacetamide following Inhalation in the Rat

Reproduction Study of Dimethylacetamide following Inhalationin the Rat. Ferenz, R. L., and Kennedy, G. L., Jr. (1986). Fundam.Appl Toxicol. 7, 132-137. Groups of 10 male and 20 female Crl:CD(SD)BRrats were exposed to vapors of dimethylacetamide (DMAC) at concentrationsof 0 (control), 30, 100, or 300 ppm. Exposures were conductedfor 6 hr/day, 5 days/week for 10 weeks (prebreeding), then 7days/week for 7 to 8 weeks (through breeding, gestation, andlactation). The exposure period was interrupted for female ratsbetween gestation Day 21 and postpartum Day 4. No compound-relatedeffects on body weight, survival, or clinical signs were detectedin parental rats. Liver weight to body weight ratios were increasedin groups where both males and females were exposed to 300 ppmbut not in groups where only males or only females were exposedto 300 ppm. No significant differences were observed betweencontrol and test rats with respect to mating performance, fertility,length of gestation, progeny numbers, structure, and viability.At 21 days postpartum, pups derived from matings involving exposureof both sexes to 300 ppm or exposure of parental females to300 ppm had lower body weights than did the controls. Grosspathologic examination of representative pups and evaluationof liver and gonad weight data did not reveal any DMAC-relatedchanges. It is concluded that reproduction in rats was not alteredby repeated inhalation exposure to up to 300 ppm DMAC.     

Some aspects relating to the evaluation of the effects of chemicals on male fertility

Reviews and studies on individual compounds were analyzed as to the suitability of different study designs and endpoints for detecting adverse effects of chemicals on male reproduction in animal species. Of the endpoints investigated, the most sensitive proved to be histopathology of the testes. Using refined histopathology, effects could be detected with a high degree of sensitivity as early as 4 weeks after treatment. Other sensitive endpoints were the weights of reproductive organs, including accessory glands, i.e., testis, epididymis, prostate, and of the seminal vesicle, as well as sperm parameters such as sperm count, sperm morphology, and sperm motility. Sperm motility was found to be in some cases more sensitive than histopathology. The above parameters showed a higher sensitivity than fertility parameters. In fact, in most cases, not only one but several endpoints were affected. Continuous breeding studies and 90-day studies with additional measurements of sperm parameters were similarly effective in detecting compounds which affect male fertility. Interspecies extrapolation factors (IEFs) have been derived for the most sensitive endpoints in laboratory animals. If the calculation is based on caloric demand and a sensitive endpoint of reproductive toxicity, many IEFs tend to be about 1, indicating that humans are generally not more susceptible to reproductive toxicants than laboratory animals. With respect to hazard identification, it is possible to detect adverse effects on male reproduction in a standard subacute study with concentrations that produce significant general toxicity. If effects are found, for the risk assessment the NOAEL has to be determined by testing specific sensitive parameters as specified above.     

Effects of tetrabromobisphenol A, brominated flame retardant, in ICR mice after prenatal and postnatal exposure.

Tetrabromobisphenol A (TBBPA), brominated flame retardant, is produced in the largest amounts globally for use in plastics or building materials. TBBPA has been detected in sediment, air at the dismantling plant or human serum samples. In the present study, we examined the effects of prenatal and postnatal exposure to TBBPA in mice. TBBPA (99.1% pure) in diet was administered to pregnant ICR mice at doses of 0% (control), 0.01%, 0.1% or 1.0% from gestational day 0 to weaning at postnatal day 27. The average daily food intake and body weight of dams showed no significant differences between the control and treated groups. There were no dose-related effects on reproductive data. Serum concentrations of total-cholesterol and liver weights of treated dams and offspring were higher than those of the control mice. Histological findings in treated dams or offspring showed the increase of focal necrosis of hepatocytes and inflammatory cell infiltration in the liver, and increase of dilation or atrophy of renal tubules and cyst in the kidney. TBBPA was developed as a new, safe class of flame retardant and was not highly toxic. However, the present data suggested that TBBPA caused a lipid metabolic disorder and hepatic or kidney lesion, under these conditions.     

Tetrabromobisphenol A (TBBPA): Possible modes of action of toxicity and carcinogenicity in rodents

Due to potential consumer exposures, the toxicity of tetrabromobisphenol A (TBBPA) has been extensively studied. Reviews of TBBPA concluded no concerns regarding human health risks. The low toxicity of TBBPA is consistent with low bioavailability. However, some oral toxicity studies in rodents with TBBPA reported changes in thyroid hormone levels and a carcinogenicity study with TBBPA showed increased incidences of uterine tumors in rats. This review analyzes several modes of action (MoA) that may account for the observed thyroxine hormone changes and the uterine tumors. It concludes that the potential modes of action for thyroid changes induced by TBBPA are expected to exhibit a threshold for adverse effects due to the ability of the mammalian organism to compensate small changes in thyroid hormone levels. Regarding MoAs for the uterine tumors, TBBPA does not exert genotoxic or estrogenic effects. Available evidence suggests that TBBPA may increase levels of circulating estrogens by a competitive inhibition of estrogen conjugation and produce uterine tumors by promoting pre-existing Tp53-mutations due to increased estrogen levels resulting in increased cell proliferation.     

In Utero Exposure to Environmentally Relevant Concentrations of PCB 153 and PCB 118 Disrupts Fetal Testis Development in Sheep

Polychlorinated biphenyls (PCB) are environmental pollutants linked to adverse health effects including endocrine disruption and disturbance of reproductive development. This study aimed to determine whether exposure of pregnant sheep to three different mixtures of PCB 153 and PCB 118 affected fetal testis development. Ewes were treated by oral gavage from mating until euthanasia (d 134), producing three groups of fetuses with distinct adipose tissue PCB levels: high PCB 153/low PCB 118 (n = 13), high PCB 118/low PCB 153 (n = 14), and low PCB 153/low PCB 118 (n = 14). Fetal testes and blood samples were collected for investigation of testosterone, testis morphology, and testis proteome. The body weight of the offspring was lower in the high PCB compared to the low PCB group, but there were no significant differences in testis weight between groups when corrected for body weight. PCB exposure did not markedly affect circulating testosterone. There were no significant differences between groups in number of seminiferous tubules, Sertoli cell only tubules, and ratio between relative areas of seminiferous tubules and interstitium. Two-dimensional (2D) gel-based proteomics was used to screen for proteomic alterations in the high exposed groups relative to low PCB 153/low PCB 118 group. Twenty-six significantly altered spots were identified by liquid chromatography (LC)–mass spectroscopy (MS)/MS. Changes in protein regulation affected cellular processes as stress response, protein synthesis, and cytoskeleton regulation. The study demonstrates that in utero exposure to different environmental relevant PCB mixtures exerted subtle effects on developing fetal testis proteome but did not significantly disturb testis morphology and testosterone production.     

Effects of housing condition on experimental outcome in a reproduction toxicity study

In most toxicity studies single housing is still preferred, as social stress is believed to have an effect on experimental outcome through interaction with the toxic compound or by increasing variation. There are also arguments that single housing will have a similar effect. In this study the qualitative and quantitative effects of single- and social housing of rats has been investigated on immune- and endocrine responses, histopathology and body- and organ weights in a one-generation endocrine disrupter study (OECD 415) in rats exposed to tetrabromobisphenol A (TBBPA). The results of this study show that differences in parameters between the housing conditions were rarely noted. Striking results of the study are that in several parameters significant differences were noted in the un-dosed control group in single versus group housed animals, meaning that TBBPA can mask or enhance housing effects, or vice versa. In one case single housing altered the effect of the toxic compound. Depending on the endpoints of the study, the type of housing condition must be taken into consideration as findings like these could have great implications for the interpretation and validity of results from toxicological assays and the number of animals needed to detect significant effects of toxic compounds.