June 24, 2005
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70 Bambra Rd Caulfield North Victoria 3161 Australia Commentary: Setting aside tradition when dealing with
endocrine disruptors
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
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
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
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
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?
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
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)


Phs 398 (rev. 9/04), biographical sketch format page

BIOGRAPHICAL SKETCH Professor, Univ. of Maryland, Baltimore Chief Scientific Officer, AllTranz Inc. EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.) University of Colorado, Boulder/Denver, CO The University of Michigan, Ann Arbor, MI University of California, San Francisco, CA Personal Statement


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