Studies and evaluation of the potential toxicity of decabromodiphenyl ethane to five aquatic and sediment organisms.

The potential toxicity of decabromodiphenyl ethane (DBDP-Ethane) was explored in 5 types of organisms residing in the water column and/or sediment, e.g. Oncorhynchus mykiss, Pseudokirchneriella subcapitata, Daphnia magna, Chironmus riparius, and Lumbriculus variegates. Fish, algae or Daphnia were unaffected by acute exposures to water accommodated fractions of 110mg DBDP-Ethane/L. Chronic exposure to DBDP-Ethane at the highest dose tested, 5000mg/kg dry sediment, did not affect midge mean development times, emergence or development rates or oligochaete survival, reproduction or dry weight. The chronic EC50, LOEC and NOEC were ≥5000mg/kg in the two sediment species. Applying an assessment factor of 50, the unbounded predicted no effect concentration (PNEC(sediment)) was 100mg/kg dry sediment. The calculated PNEC indicates DBDPE-Ethane presents little risk to sediment organisms. These results add to DBDP-Ethane's existing database in the terrestrial compartment and mammals.

Terrestrial toxicity evaluation of decabromodiphenyl ethane on organisms from three trophic levels.

Decabromodiphenyl ethane (DBDP-Ethane) was evaluated for its potential to effect sewage sludge respiration, soil nitrification, survival and reproduction in Eisenia fetida, and seedling emergence and growth in Zea mays, Lolium perenne, Glycine max, Allium cepa, Lycopersicon esculentum, and Cucumis sativa. The no observed effect concentrations (NOECs) were identified at the limit concentration level for sewage sludge respiration (>10 mg DBDP-Ethane/kg dry soil), >2500 mg/kg dry soil for soil nitrification, >3720 mg/kg dry soil for earthworm survival, and >6250 mg/kg dry soil for seedling emergence and growth in Z. mays, L. perenne, and G. max . Treatment-related effects were identified for E. fetida reproduction, C. sativa survival, and L. esculentum and A. cepa height and dry weight. The most sensitive endpoints were decreased height and dry weight for A. cepa and decreased reproduction for E. fetida with NOECs of 1563(nominal) (1540(measured)) and 2210(nominal) (1907(mean measured)) mg/kg dry soil. The NOEC for soil nitrification and the lowest NOEC identified for soil (i.e., A. cepa) were used to derive predicted no effect concentrations (PNEC) values of 2500 mg/kg for sewage sludge and 156 mg/kg for soil. The calculated PNECs indicate DBDP-Ethane presents little risk to organisms in the sewage sludge and soil compartments.

Industry-sponsored research on the potential health and environmental effects of selected brominated flame retardants.

Modern fire-fighting techniques, equipment and fire-resistant building design has lead to less destruction than in the previous centuries. However, a high fuel load in either a residence or a commercial building can overwhelm even the best firefighters or building construction, and factors affecting the fuel load have changed in recent decades. The fire load in a typical home has doubled over the last 50 years, furnishings typically include those made of petrochemicals that can behave as if containing built-in accelerant, and modern energy-efficient buildings are less able to disperse heat in the event of a fire. Flame retardant chemicals (FRs) are one means used to reduce the risk of fire. FRs are typically added or incorporated chemically into a polymer to slow or hinder the ignition or growth of a fire in low-to-moderate cost commodity polymers. One type of FR contains bromine atoms as the active moiety. The FR industry, either as individual companies or as consortia, has conducted a broad range of studies on the commercial deca-, octa- and pentabromodiphenyl oxide/ether, tetrabromobisphenol A and hexabromocyclododecane products. These five products have data in excess of the OECD Screening Informational Data Set (SIDS) and the U.S. High Production Volume (HPV) program, and sufficient data for the performance of formal EU risk assessments. The objective of this paper is to present the range of data developed by industry consortia and to provide sources for the information. We hope to facilitate further research by assembling references to industry consortia-sponsored research here.

The subchronic oral toxicity of ethane, 1,2-bis(pentabromophenyl) (Saytex 8010) in rats.

Ethane, 1,2-bis(pentabromophenyl) (EBP; CAS no. 8452-53-9) dose levels of 0, 100, 320 and 1000 mg/kg/day administered to rats by gavage in corn oil for 90 consecutive days produced no compound-related clinical signs of systemic toxicity, ocular lesions, or alterations in urinalysis, clinical chemistry, and hematology values in the treated or recovery groups. No biologically or toxicologically significant differences were observed in body weights, body weight gains, and food consumption. Statistically significant differences were found between control and high-dose animals in mean absolute or relative liver weights. Histomorphological evaluation showed in male rats low-grade liver changes consisting of minimal to slight hepatocellular vacuolation (high-dose males) and minimal to slight centrilobular hepatocytomegaly (high- and possibly mid-dose males). These changes had resolved by the end of the 28-day recovery period. No treatment-related changes were found in the livers of female rats. No treatment-related histomorphologic changes were present in any of the other tissues examined in either sex, except for evidence of aspirated test article in individual rats. The 90-day EBP no-adverse-effect level in the rat was > or = 1000 mg/kg/day, and was consistent with that of the preceding 28-day study (no-effect level > or = 1250 mg/kg/day). EBP's lack of toxicity is likely related to poor bioavailability due to its high molecular weight and low solubility.

Prenatal oral (gavage) developmental toxicity study of decabromodiphenyl oxide in rats.

Decabromodiphenyl oxide (DBDPO) is a highly effective flame retardant that is primarily used in electrical and electronic equipment with a secondary, but important, application in upholstery textiles. DBDPO, the second largest volume brominated flame retardant in use today, has undergone a wide range of toxicology tests in mammalian species with the results indicating a no-adverse-effect level of approximately 1000 mg/kg/day in oral repeated-dose studies. An oral prenatal developmental toxicity study of the commercial DBDPO product (97% purity) was performed under current EPA OPPTS and OECD guidelines. Female Sprague-Dawley rats (25 mated females/group) received 0,100, 300 or 1000 mg DBPDO/kg/ day via gavage in corn oil during gestation days 0 through 19. All females survived until scheduled sacrifice. No clinical signs of toxicity were observed. Pregnancy rates in the control and treated groups ranged from 96% to 100% and provided 23 or more litters in each group for evaluation on gestation day 20. No effect of treatment was seen in maternal gestational parameters (body weight, body weight gain, and food consumption), uterine implantation data, liver weight, or necropsy findings. Likewise, no effect of treatment was seen in fetal body weights, fetal sex distribution, or during the fetal external, visceral, or skeletal examinations. The NOEL (no-observable-effect level) for maternal and developmental toxicity was 1000 mg DBPDO/kg/day, the highest dose level administered on gestation days 0 to 19.

A comparison of the properties of the major commercial PBDPO/PBDE product to those of major PBB and PCB products.

Decabromodiphenyl oxide (DBDPO), a highly effective polybrominated diphenyl oxide (PBDPO) flame retardant (FR) used primarily in electrical and electronic equipment, is the second highest volume brominated flame retardant (BFR) and accounts for 82% of the PBDPO usage globally. The apparent similarities in chemical structure between the DBDPO, polychlorinated and polybrominated biphenyl (PCB, PBB) molecules have led to the presumption that these substances also share similar toxicological and environmental properties. However, DBDPO's physical/chemical properties, applications, environmental release, and toxicology differ substantially from the former PCB/PBB products. DBDPO is a heavier and larger molecule than components of the predominant PCB/PBB products used in the past, and the commercial DBDPO product has a lower water solubility and vapor pressure than the former PCB and PBB products. DBDPO's detection in the environment is generally in sediments near known point sources, and its primary use in thermoplastics limits its environmental release from end products. PBB environmental release has been primarily associated with one accident occurring in the US in 1973. The PCBs, used in applications with a high potential for environmental release, were detected in diverse locations around the world as early as in the 1970s. Current releases of PCB are considered related to an environmental cycling process of congeners previously released into the environment; however, DBDPO's physical/chemical properties do not indicate a similar potential. Extensive testing of the DBDPO commercial product has demonstrated that it is toxicologically and pharmacokinetically different from the predominant PCB and PBB products used in the past. Thus, although the chemical structures of DBDPO, PBB, and PCB appear similar, the properties of DBDPO are distinctly different.

The toxicology of the three commercial polybrominated diphenyl oxide (ether) flame retardants.

Three commercial polybrominated diphenyl oxide flame retardants (PBDPO, PBDE) are manufactured: decabromodiphenyl oxide (DBDPO), octabromodiphenyl oxide (OBDPO) and pentabromodiphenyl oxide (PeBDPO). The composition, production volumes, uses and toxicology of the three products differ. In 1999, DBDPO accounted for approximately 82% of the global PBDPO usage. DBDPO has been extensively tested. DBDPO was not acutely toxic, was not irritating to the skin or eye, and did not induce skin sensitization. No evidence of genotoxic effects was detected in the Ames Salmonella, chromosome aberration, mouse lymphoma, or sister chromatid exchange tests. No cytogenic changes were observed in the bone marrow of rats (parents and offspring) undergoing a one-generation reproduction test. DBDPO did not adversely affect development or reproduction in rats. DBDPO's no-adverse-effect-level (NOAEL) in repeated dose studies was > or = 1000 mg/kg body weight. No, equivocal, or some evidence of carcinogenicity, dependent on genus and sex, was found in mice and rats at 2.5% and 5% of the diet administered for 2 years. DBPDO was poorly absorbed from the gastrointestinal tract (< 0.3-2% oral dose), had a short half-life (< 24 h) compared to PCB 153 (only 2% of an oral dose eliminated by rats in 21 days), and was rapidly eliminated via the feces (> 99% in 72 h). In contrast, components of the PeBDPO product were well absorbed and slowly eliminated, OBDPO's effect level in a 90-day study was approximately 100 mg/kg, PeBDPO's no-effect-level (NOEL) in a 30-day study was 1 mg/kg, and OBDPO induced developmental toxicity in the rat. In aquatic species, neither DBDPO nor OBDPO were toxic to aquatic organisms or bioconcentrating. Components of the PeBDPO product bioconcentrated in fish but produced little evidence of adverse effects.

Herbs of special interest to women.

OBJECTIVE: To review the efficacy and safety of specific herbal medications that have been used traditionally to treat common conditions in women. DATA SOURCES: Current literature, with emphasis on more rigorously controlled studies. DATA SYNTHESIS: Herbal medicines have long been used in traditional healing systems to treat conditions of particular interest to women, such as premenstrual syndrome (PMS) and menopausal symptoms. For a select number of phytomedicines, including evening primrose oil, black cohosh root extract, dong quai, and chaste tree berry, scientific investigation is elucidating the pharmacologically active constituents, mechanism of action, and clinical value. CONCLUSION: Based on the available evidence, evening primrose oil and chaste tree berry may be reasonable treatment alternatives for some patients with PMS. Dong quai may have some efficacy for PMS when used in traditional Chinese multiple-herb formulas. For relief of menopausal symptoms, black cohosh root extract and dong quai have good safety profiles, but only black cohosh has demonstrated efficacy for this indication. Safety data, especially during pregnancy and lactation, are still largely lacking for many herbal medications, and recommendations for usage and dosage vary. Pharmacists who wish to recommend herbal products for women's health conditions need to evaluate the scientific literature in order to form their own opinions about appropriate use and safety.

The in vivo oxidative metabolism of 2,4- and 2,6-dimethylaniline in the dog and rat.

The xylidine 2,4-dimethylaniline (2,4-DMA) produces hepatic cholangiofibrosis, bile duct proliferation, and foci of cellular hyperplasia and degeneration in the rat. The same compound is relatively innocuous in the dog. 2,6-Dimethylaniline (2,6-DMA) does not produce hepatic lesions in the rat, except at high doses but is a potent inducer of fatty degeneration in the dog. The purpose of the present study was to examine pathways of in vivo metabolism of both isomers in the rat and dog. The major urinary metabolite of 2,4-DMA in the rat was N-acetyl-4-amino-3-methylbenzoic acid (AAMBA) while in the dog it was 6-hydroxy-2,4-dimethylaniline (6-HDMA). The dog also produced a smaller amount of unacetylated 4-amino-3-methylbenzoic acid (4-AMBA) and its glycine conjugate. 2,6-DMA was metabolized principally to 4-hydroxy-2,6-dimethylaniline (4-HDMA) in both species, but the dog also produced significant quantities of 2-amino-3-methylbenzoic acid (2-AMBA), along with trace amounts of the glycine conjugate of the latter and 2,6-dimethylnitrosobenzene. Trace levels of an unknown postulated to be 3,5-dimethyl-4-imino-quinone were also found in urine of dogs. In rats, repeated administration of either xylidine for 10 days failed to increase the appearance of metabolites, but 3-methylcholanthrene (3-MC) did increase the urinary concentration of AAMBA in 2,4-DMA dosed rats. The divergent pathways of metabolism in the 2 species could be responsible for species specific pathologies produced by these 2 xylidines.

Covalent binding of [14C]-2,6-dimethylaniline to DNA of rat liver and ethmoid turbinate.

The xylidide 2,6-dimethylaniline (2,6-DMA) has produced carcinomas and papillary adenomas in the nasal cavity of rats at high dietary doses (3000 ppm) in a 2-yr bioassay. The objective of the present study was to measure the covalent binding of 2,6-DMA to DNA of rat ethmoid turbinate tissues and, for comparison, to DNA of rat liver. The potent hepatocarcinogen 2-acetylaminofluorene (AAF) was studied as a positive control for adduct formation and covalent binding index (CBI) calculation. Both 2,6-DMA and AAF were administered as 14C-(ring)-labeled agents to naive rats and to rats pretreated for 9 d with unlabeled 2,6-DMA or AAF. The CBI value for 2,6-DMA adduct formation with ethmoid turbinate DNA was below the assay's sensitivity limit in nonpretreated rats, but increased to 41.9 in rats pretreated with unlabeled 2,6-DMA. It also increased from 0.6 in nonpretreated to 7.9 in liver of pretreated rats. The opposite pattern, however, was observed for AAF. In nonpretreated rats considerable adduct formation was observed in liver (CBI = 271.5) and modest values (CBI = 39.3) were calculated for ethmoid turbinate tissues. Pretreatment with unlabeled AAF caused a significant decrease in CBI values, to 18.3 for liver and less than 0.5 for ethmoid turbinate. The results suggest that there may be value in conducting DNA covalent binding assays in both naive animals and animals pretreated with the test article.

The nephrotoxic potential of gentamicin in the cat: enzymuria and alterations in urine concentrating capability.

This study investigated the potential for nephrotoxicity of gentamicin in cats by measuring marker enzyme concentrations, [Na], [K], osmolality, and pH of the urine, and blood urea nitrogen (BUN) levels. Gentamicin was administered i.m. at 4.4 mg/kg once daily (s.i.d.) or twice daily (b.i.d.) for 7 days. Concentrations of lactic dehydrogenase (LDH), lysozyme (LZM), alkaline phosphatase (AP), and glutamate dehydrogenase (GD) were measured as total 24-h excretions. The s.i.d. regimen produced only a slight increase in LDH excretion after 5 days, whereas the b.i.d. regimen caused an increase in the excretion of all enzymes. The greatest elevations were observed for LZM and LDH. Of the enzymes studied, these appeared to be the most appropriate to monitor for potential nephrotoxicity, except that urinary concentrations did not correlate well with duration of gentamicin administration. Only slight elevations in BUN were observed for either regimen. Single daily administration increased urine osmolality slightly, but b.i.d. treatment caused a marked and immediate decrease in urine osmolality, [Na], and total Na excretion. Urinary [K] was also depressed, as was total K excretion after 6 days. Urine pH was not substantially affected. This study showed that the recommended daily dose of 4.4 mg/kg produced little if any evidence of nephrotoxicity as indicated by the parameters measured. Twice daily dosing, however, produced elevations in urine enzyme concentrations, and markedly decreased urine osmolality and Na and K excretion. Compared to other species studied, the cat appears particularly sensitive to urine concentrating alterations resulting from repeated gentamicin administration.