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Commentary: Setting aside tradition when dealing with endocrine disruptors 2005-05-18
In 1996, the US Congress directed the Environmental Protection Agency to produce screens and assays to detect estrogenic and other endocrine-
disrupting chemicals in food and water. To date, there are none. Years have been wasted in attempts to utilize traditional toxicological approaches to
solve the problem, when in retrospect, it is now apparent that the delay in part stems from the reluctance to attack the problem with entirely new approaches. To develop new testing protocols, it is necessary to set aside
much of the dogma of toxicology and to begin again with open minds. A few pertinent examples are provided concerning what has been overlooked and
what needs to be done. In particular, it is necessary to give close attention to the selection of animal strain and diet, factors that were only loosely
controlled historically when one takes into consideration what has been learned in the last decade. Vast numbers of animals have been sacriﬁced,
and more will be sacriﬁced, in futile attempts to validate assays and to develop safety standards unless knowledge gained over the past decade
concerning the sensitivity and complexity of the endocrine system is taken into consideration.
Authors: Colborn, Theo Full source: ILAR Journal 2004, 45(4), 394-400 (Eng)
Selegiline Transdermal System (STS): Preclinical Assays of Dermal Safety 2005-05-18
Two preclinical sensitization studies were conducted to determine the potential for allergic contact dermatitis with the selegiline transdermal
system (STS), a novel transdermal system being developed to treat major depressive disorder. These included a qualitative structure-activity
relationship (QSAR) analysis to assess the allergic dermatitis potential of selegiline, and a guinea pig dermal sensitization study to determine the
delayed contact hypersensitivity potential of the STS. In the QSAR analysis, selegiline was classiﬁed as a nonallergen. In the guinea pig study, the STS was found not to act as a dermal sensitizer. Thus, based upon the results of these two preclinical studies, treatment with the STS is unlikely to pose a risk of causing signiﬁcant allergic contact dermatitis. Human data, reported elsewhere, support this hypothesis. Authors: Pauporte, Michele; Goodhead, Melissa; Azzaro, Albert J.; Moonsammy, George; Maibach, Howard Full source: Journal of Toxicology, Cutaneous and Ocular Toxicology 2004, 23(3), 173-178 (Eng)
Selegiline Transdermal System (STS): Assessments of Dermal Safety in Human 2005-05-18 The selegiline transdermal system (STS) is being developed to treat major depressive disorder. In a Phase I clinical study, the STS (20 mg/20 cm2) produced mild dermal irritability and demonstrated a low potential for contact allergenicity. In Phase III multicenter studies in major depression, over 1800 patients have been evaluated for dermal safety to reveal an overall rate of application site reactions (ASRs) with STS of 21.8% compared with a placebo rate of 9.7%. Discontinuation rates due to dermal adverse events in clinical studies were low (3.5%). Overall, the STS demonstrated good tolerability
regarding ASRs and the potential for delayed contact hypersensitivity. Authors: Pauporte, Michele; Azzaro, Albert J.; Moonsammy, George; Maibach, Howard Full source: Journal of Toxicology, Cutaneous and Ocular Toxicology 2004, 23(3), 179-187 (Eng)
Incorporation of Therapeutic Interventions in Physiologically Based Pharmacokinetic Modeling of Human Clinical Case Reports of Accidental or Intentional Overdosing with Ethylene Glycol 2005-05-18 Although occupational uses of the high production volume (HPV) chemical ethylene glycol (EG) have not been associated with adverse effects, there are case reports where humans have either intentionally or accidentally ingested large quantities of EG, primarily from antifreeze. The acute toxicity of EG can proceed through three stages, each associated with a different metabolite: central nervous system depression (ethylene glycol), cardiopulmonary effects associated with metabolic acidosis (glycolic acid), and ultimately renal toxicity (oxalic acid), depending on the total amounts consumed and the effectiveness of therapeutic interventions. By integrating the case report data sets with controlled studies in this PBPK model, it was demonstrated that fomepizole, if administered early enough in a clinical situation, can be more effective than ethanol or hemodialysis in preventing the metabolism of EG to more toxic metabolites. Hemodialysis remains an important option, however, if treatment is instituted after a signiﬁcant amount of EG is metabolized or if renal toxicity has occurred. Authors: Corley, R. A.; McMartin, K. E. Full source: Toxicological Sciences 2005, 85(1), 491-501 (Eng) Development of a Physiologically Based Pharmacokinetic Model for Ethylene Glycol and Its Metabolite, Glycolic Acid, in Rats and Humans
2005-05-18 An extensive database on the toxicity and modes of action of ethylene
glycol (EG) has been developed over the past several decades. Although renal toxicity has long been recognized as a potential outcome, in recent
years developmental toxicity, an effect observed only in rats and mice, has become the subject of extensive research and regulatory reviews to
establish guidelines for human exposures. The developmental toxicity of EG has been attributed to the intermediate metabolite, glycolic acid
(GA), which can become a major metabolite when EG is administered to rats and mice at high doses and dose rates. Therefore, a physiological based pharmacokinetic (PBPK) model was developed to integrate the
extensive mode of action and pharmacokinetic data on EG and GA for use in developmental risk assessments. The resulting PBPK model includes
inhalation, oral, dermal, i.v., and s.c. routes of administration. Metabolism of EG and GA were described in the liver with elimination via the kidneys.
When internal dose surrogates were compared in rats and humans over a broad range of exposures, it was concluded that humans are unlikely to
achieve blood levels of GA that have been associated with developmental toxicity in rats following occupational or environmental exposures. Authors: Corley, R. A.; Bartels, M. J.; Carney, E. W.; Weitz, K. K.; Soelberg, J. J.; Gies, R. A.; Thrall, K. D. Full source: Toxicological Sciences 2005, 85(1), 476-490 (Eng)
Neurobiological impact of environmental estrogens 2005-05-18 This paper provides an introduction to a special issue dedicated to the action of environmental estrogens on neural circuits and behavior. The problem of endocrine disrupting chemicals (EDCs), i.e. chemicals that have the capacity to interfere with the endocrine system, has gained increasing attention as it has become clear that these environmental contaminants may be active in humans, as well as in wildlife and domestic animal species. The majority of the early investigations were aimed at the discovery of the toxicol. effects of the EDCs, but biomedical observations were among some of the ﬁrst indications that estrogenic compounds may exert deleterious effects, even some time after exposure. The data derived from women exposed prenatally to diethylstilbesterol provided powerful evidence for long-term effects and endocrine disruption associated with selected compounds. The examination of wild animal populations exposed to industrial chemicals showed that the chemical exposure, though nonlethal, left the individual impaired or even incapable of reproducing. Among the multiple targets of the action of EDCs, several researches performed in recent years have investigated subtle modiﬁcations of the animal behaviors (reproductive, aggressive) that are likely to be related to alterations of speciﬁc neural pathways. Authors: Panzica, G. C.; Viglietti-Panzica, C.; Ottinger, M. A. Full source: Brain Research Bulletin 2005, 65(3), 187-191 (Eng) Biochemical toxicity of benzene
2005-05-18 Human exposure to benzene in work environment is a global occupational
health problem. After inhalation or absorption, benzene targets organs like liver, kidney, lung, heart and brain etc. It is metabolized mainly in the
liver by cytochrome P450 multifunctional oxygenase system. Benzene causes haematotoxicity through its phenolic metabolites that act in concert to produce DNA strand breaks, chromosomal damage, sister chromatid
exchange, inhibition of topoisomerase II and damage to mitotic spindle. The carcinogenic and myelotoxic effects of benzene are associated with
free radical formation either as benzene metabolites or lipid peroxidation products. Benzene oxide and phenol have been considered as proheptons.
Liver microsomes play an important role in biotransformation of benzene whereas in kidney, it produces degenerative intracellular changes. Cohort
studies made in different countries suggest that benzene induces multiple myeloma in petrochemical workers. Though extensive studies have
been performed on its toxicity, endocrinal disruption caused by benzene remains poorly known. Transgenic cytochrome P450 IIE1 mice may help in understanding further toxic manifestations of benzene. Authors: Rana, S. V. S.; Verma, Yeshvandra Full source: Journal of Environmental Biology 2005, 26(2), 157-168 (Eng)
Withdrawal of rofecoxib (Vioxx): What about cardiovascular safety of COX-2 selective non-steroidal anti-inﬂammatory drugs? 2005-05-18 Rofecoxib (Vioxx), the ﬁrst COX-2 selective non-steroidal anti-inﬂammatory drug (NSAID), was recently withdrawn by Merck Sharp & Dohme. Indeed, both observational studies and randomized clinical trials showed that rofecoxib is associated with a signiﬁcantly increased risk of acute myocardial infarction in patients receiving either high daily dosage (>25 mg/day) or for a long period of time (> 18 mo). The precise mechanism responsible for this
phenomenon still remains unknown. Currently available data suggest that this adverse effect is not observed with other COX-2 NSAIDs, especially celecoxib for which the information is most abundant. Nevertheless, caution is required because of lack of prospective long-term data, and strict respect of indications and modalities of clinical use of COX-2 NSAIDs is mandatory. Finally, in patients with high cardiovascular risk who should receive a COX-2 selective NSAID, the association with a low dose of acetylsalicylic acid is recommended in order to beneﬁt of a protective antiplatelet effect. Authors: Scheen, A. J. Full source: Revue Medicale de Liege 2004, 59(10), 565-569 (Fr)
Health effects of exposure to waste incinerator emissions: A review of epidemiological studies 2005-05-18
This review evaluates the epidemiological literature on health effects in relation to incineration facilities. Several adverse health effects were reported.
Signiﬁcant exposure-disease associations are reported by 2/3 of the papers focusing on cancer (lung and larynx cancer, non-Hodgkin’s lymphoma).
Positive associations were found for congenital malformations and residence near incinerators. Exposure to PCB and heavy metals were associated with
several health outcomes and in particular with reduction of thyroid hormones. Findings on non-carcinogen pathologies are inconclusive. Effect of biases and confounding factors must be considered in the explanation of ﬁndings.
Methodological problems and insufﬁcient exposure information generate difﬁculties on study results. Research needs include a better deﬁnition of
exposure in qualitative and quantitative terms in particular by developing the use of biomarkers and by implementing environmental measurements.
Authors: Franchini, Michela; Rial, Michela; Buiatti, Eva; Bianchi, Fabrizio Full source: Annali dell’Istituto Superiore di Sanita 2004, 40(1), 101-115 (Eng)
The UK government is building a national database of medical records, aproject which many doctors oppose; in a Medix poll in November, over half ofall GPs said they would not upload their patients’ data without consent  . The following week, a Joseph Rowntree Reform Trust poll revealed that 53% ofpatients oppose a central medical records database with no right to opt out. A campaign, The
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