Lels of the polybrominated diphenyl ethers (PBDEs), a class of widely used flame retdants, appear to be rising rapidly in human tissues, as evidenced by studies of human breast milk The case of the PBDEs illustrates the value of breast-milk monitoring programs in idendfying important emerging pollutants, and highlights why such monitoring programs are needed in the United States. A review of the use, occurrence, and toxicity of PBDEs indicates many parallels between some PBDEs, PCBs, and other polyhalogenated persistent organic pollutants, and suggests that the PBDEs may be a significant environmentl challee in the future. Key wordk breast-milk monitoring programs, flame r d , persistent organic pollutants, polybrominated diphenyl ethers, polychlorinated biphenyls, polychlorinated diphenyl ethers, structure-activity relationships, toxicity.
Summary. PEGylation is the technology involving the covalent attachment of polyethylene glycol (PEG) to a protein-, peptide-or small-molecule drug to improve their pharmacokinetic, pharmacodynamic and immunological profiles, and thus, enhance the therapeutic effect. Today, PEGylation of proteins is a well-established technology and is being used in the treatment of a variety of clinical disorders. Several PEGylated coagulation proteins for haemophilia A and B are under development with the goal of prolonging the circulation half-life of factor VIII (FVIII) or factor IX. The prolongation of half-life, resulting in less frequent injections can provide significant benefits in improving the quality of life of subjects with haemophilia and improvement in adherence to treatment. A review of published literature on PEGylated therapeutic products currently approved for human use and a discussion of a PEGylated recombinant FVIII molecule (BAY 94-9027, Bayer HealthCare, Berkeley, CA, USA) currently being investigated in the pivotal clinical trial prior to registration is provided. Available safety information of PEGylated proteins containing high molecular weight PEG does not indicate any safety concerns to date, following long-term (chronic) use in animal models or patients. Chronic use of currently available PEGylated products has been shown to be safe, paving the way for chronic use of PEGylated coagulation products in persons with haemophilia.
Recent analyses have revealed that 38% of municipal sources of drinking water in California have detectable levels of hexavalent chromium. This observation provided new impetus to characterize the carcinogenic risk associated with oral exposure to hexavalent chromium in drinking water. Notwithstanding the well-characterized increases in cancer associated with inhalation exposure to this chemical, the marked reduction of hexavalent chromium to trivalent chromium in the stomach suggests that exposure to hexavalent chromium in drinking water may not pose a carcinogenic risk. A reevaluation of studies that investigated the toxicokinetics, the genotoxicity, and the mechanism of carcinogenicity of hexavalent chromium, as well as the available human and animal cancer studies, was undertaken to determine if there is evidence that exposure to this chemical in drinking water may pose a carcinogenic risk. Mechanistic studies suggest the potential for a carcinogenic response if hexavalent chromium enters cells. Both toxicokinetic and genotoxicity studies indicate that a portion of an orally administered dose of hexavalent chromium is absorbed and gets into cells of several tissues, causing DNA damage. The only lifetime oral study of hexavalent chromium in animals conducted thus far yielded a statistically significant increase in stomach tumors compared to controls. Also, in a limited-term cancer study, co-exposure to hexavalent chromium in drinking water and ultraviolet light produced skin tumors in mice. The only available cancer study of humans exposed to hexavalent chromium in drinking water revealed a statistically significant increase in stomach tumors. Moreover, a meta-analysis of occupational studies also revealed a statistically significant increase in stomach cancers. The increases in stomach tumors in both human and animal studies, along with the toxicokinetic, genotoxic, and mechanistic data, suggest that oral exposure to this agent appears to pose a carcinogenic risk.
Data on Polybrominated diphenylether (PBDE) concentrations in individual U.S. women were compiled. PBDE levels in adipose tissue, serum, and breast milk from individual U.S. women were found to follow similar lognormal distributions, which exhibited a high degree of variability. The distribution of lipid-normalized PBDE concentrations for all media combined had a median of 47.9 ng/g and a 95th percentile estimate of 302 ng/g. Estimates of congener-specific kinetic parameters were used to calculate the total daily intake of the PBDEs (sum of 5 PBDE prominent congeners, PBDE-47, -99, -100, -153, and -154) that would be required to achieve the measured body burdens. PBDE intake estimates from all routes of exposure were 8.5 ng/kg/d (median) and 54 ng/kg/d (95th percentile). The potential health risks posed by the PBDEs were examined by comparing 95th percentile tissue concentrations in humans (C(human)) to modeled and measured tissue concentrations in rodents that caused no developmental neurotoxicity and reproductive effects (C(rodent)). The ratio of rodent-to-human PBDE concentrations (C(rodent):C(human)) was <1 for alterations of male and female reproductive organs in rats, <10 for neurodevelopmental effects in mice, and <100 for neurodevelopmental effects in rats. If humans are as sensitive as animals to PBDE-induced developmental toxicity, the current margin of safety appears low for a fraction of the population.
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