Lethal Potency Research Articles

O34. TGF-β signaling maintains tumorigenicity of glioma-initiating cells through the Sox4–Sox2 axis

Recent studies have identified essential signaling pathways for retention of cancer stem cells in various types of cancer. We show here that autocrine TGF-β signaling plays essential roles in retention of stemness of glioma-initiating cells. TGF-β induced expression of Sox2, and this induction was mediated by Sox4, a novel, direct target gene of TGF-β. Inhibitors of TGF-β signaling resulted in deprivation of tumorigenicity of glioma-initiating cells through induction of their differentiation, and these effects were attenuated in glioma-initiating cells transduced with exogenous Sox2 or Sox4. Furthermore, glioma-initiating cells pre-treated with a TGF-β signaling inhibitor exhibited less tumorigenic activity and lethal potency in an intracranial transplantation assay. To target cancer stem cells in clinical situations, elucidation of differences between cancer stem cells and normal stem cells, and identification of novel targets which can eradicate cancer stem cells without affecting normal stem cells will be important. We show that the regulatory mechanism of the Sox axis in glioma-initiating cells is distinct from that in neural progenitor cells. Our findings suggest important differences between glioma-initiating cells and neural progenitor cells, and may open the way to depriving glioma-initiating cells of the tumorigenic activity with minimally affecting normal brain tissues (Ikushima et al., 2009). Ikushima, H., et al., 2009. Autocrine TGF-βsignaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell 5 (5), 504–514.

Snake Venomics of the Central American Rattlesnake Crotalus simus and the South American Crotalus durissus Complex Points to Neurotoxicity as an Adaptive Paedomorphic Trend along Crotalus Dispersal in South America

We report a comparative venomic and antivenomic characterization of the venoms of newborn and adult specimens of the Central American rattlesnake, Crotalus simus, and of the subspecies cumanensis, durissus, ruruima, and terrificus of South American Crotalus durissus. Neonate and adult C. simus share about 50% of their venom proteome. The venom proteome of 6-week-old C. simus is predominantly made of the neurotoxic heterodimeric phospholipase A(2) (PLA(2) crotoxin) (55.9%) and serine proteinases (36%), whereas snake venom Zn(2+)-metalloproteinases (SVMPs), exclusively of class PIII, represent only 2% of the total venom proteins. In marked contrast, venom from adult C. simus comprises toxins from 7 protein families. A large proportion (71.7%) of these toxins are SVMPs, two-thirds of which belong to the PIII class. These toxin profiles correlate well with the overall biochemical and pharmacological features of venoms from adult (hemorrhagic) and newborn (neurotoxic) C. simus specimens. The venoms of the South American Crotalus subspecies belong to one of two distinct phenotypes. C. d. cumanensis exhibits high levels of SVMPs and low lethal potency (LD(50)), whereas C. d. subspecies terrificus, ruruima, and durissus have low SVMP activity and high neurotoxicity to mice. Their overall toxin compositions explain the outcome of envenomation by these species. Further, in all C. simus and C. durissus venoms, the concentration of neurotoxins (crotoxin and crotamine) is directly related with lethal activity, whereas lethality and metalloproteinase activity show an inverse relationship. The similar venom toxin profiles of newborn C. simus and adult C. durissus terrificus, ruruima, and durissus subspecies strongly suggests that the South American taxa have retained juvenile venom characteristics in the adult form (paedomorphism) along their North-South stepping-stone dispersal. The driving force behind paedomorphism is often competition or predation pressure. The increased concentration of the neurotoxins crotoxin and crotamine in South American rattlesnake venoms strongly argues that the gain of neurotoxicity and lethal venom activities to mammals may have represented the key axis along which overall venom toxicity has evolved during Crotalus durissus invasion of South America. The paedomorphic trend is supported by a decreasing LNC (lethal neurotoxicity coefficient, defined as the ratio between the average LD(50) of the venom and the crotoxin + crotamine concentration) along the North-South axis, coincident with the evolutionary dispersal pattern of the Neotropical rattlesnakes. The indistinguisable immunoreactivity patterns of Costa Rican and Venezuelan polyvalent antivenoms toward C. simus and C. durissus venoms strongly suggest the possibility of using these antivenoms indistinctly for the management of snakebites by adult C. simus and by certain C. d. cumanensis populations exhibiting a hemorrhagic venom phenotype. The antivenomic results also explain why the antivenoms effectively neutralize the hemorrhagic activity of adult C. simus venoms but does not protect against adult C. durissus sp. and newborn C. simus envenomations. The identification of evolutionary trends among tropical Crotalus, as reported here, may have an impact in defining the mixture of venoms for immunization to produce an effective pan-American anti-Crotalus antivenom.

Autocrine TGF-β Signaling Maintains Tumorigenicity of Glioma-Initiating Cells through Sry-Related HMG-Box Factors

Despite aggressive surgery, radiotherapy, and chemotherapy, treatment of malignant glioma remains formidable. Although the concept of cancer stem cells reveals a new framework of cancer therapeutic strategies against malignant glioma, it remains unclear how glioma stem cells could be eradicated. Here, we demonstrate that autocrine TGF-beta signaling plays an essential role in retention of stemness of glioma-initiating cells (GICs) and describe the underlying mechanism for it. TGF-beta induced [corrected] expression of Sox2, a stemness gene, and this induction was mediated by Sox4, a direct TGF-beta target gene. Inhibitors of TGF-beta signaling drastically deprived tumorigenicity of GICs by promoting their differentiation, and these effects were attenuated in GICs transduced with Sox2 or Sox4. Furthermore, GICs pretreated with TGF-beta signaling inhibitor exhibited less lethal potency in intracranial transplantation assay. These results identify an essential pathway for GICs, the TGF-beta-Sox4-Sox2 pathway, whose disruption would be a therapeutic strategy against gliomas.

Characterization of the metabolic actions of crude versus dispersed oil in salmon smolts via NMR-based metabolomics

With maritime transport of crude oil from Alaska to California, there is significant potential for a catastrophic spill which could impact migrating salmon. Therefore, this study compared the lethal and sublethal metabolic actions of the water-accommodated fraction (WAF) and the chemically enhanced WAF (CEWAF, via Corexit 9500) of Prudhoe Bay crude oil in smolts of Chinook salmon ( Onchorhyncus tshawytscha). After 96-h exposure to the CEWAF, the resulting LC50 was some 20 times higher (i.e., less toxic) than that of the WAF. Muscle and liver samples from surviving fish were collected and low-molecular weight metabolites were analyzed using one-dimensional 1H and projections of two-dimensional 1H J-resolved NMR. Principal component analysis (PCA), employed to analyze NMR spectra and identify most variance from the samples, revealed age-related metabolic changes in the fish within the replicated studies, but few consistent metabolic effects from the treatments. However, ANOVA results demonstrated that the dose–response metabolite patterns are both metabolite- and organ-dependent. In general, exposure to either WAF or CEWAF resulted in an increase of amino acids (i.e., valine, glutamine and glutamate) and a decrease of both organic osmolytes (i.e., glycerophosphorylcholine) and energetic substrates (i.e., succinate). The simultaneous increase of formate and decrease of glycerophosphorylcholine in the liver, or the decrease of glycerophosphorylcholine in muscle, may serve as sensitive sublethal biomarkers for WAF or CEWAF exposures, respectively. In conclusion, dispersant treatment significantly decreased the lethal potency of crude oil to salmon smolts, and the NMR-based metabolomics approach provided a sensitive means to characterize the sublethal metabolic actions.

Consensus sequence L/PKSSLL mimics crucial epitope on Loop III of Taiwan cobra cardiotoxin

Phage display is effective in screening peptides that mimic venom’s neutralizing epitopes. A phage display cyclized heptapeptide library (C7C library) was panned with purified divalent antivenin IgG, which neutralizes Naja naja atra venom (NAV) and Bungarus multicinctus venom (BMV). The selected heptapeptide sequences were aligned with known protein sequences of NAV and BMV in GenBank. One of the four consensus sequences, L/PKSSLL, mimicked the crucial epitope on Loop III of Taiwan cobra cardiotoxin that is associated with the venom’s lethal potency. In dot blot analysis, several clones showed varying reactivities for NAV monovalent antivenin and lesser cross-reactions with BMV monovalent antivenin. The KSSLLRN-carrying phage occurred four times in selected clones and showed the strongest reactivity to NAV monovalent antivenin. Furthermore, the QDSLLPS-carrying phage also presented significant dot blot signal, indicating that the SLL sequence shared by these two clones may be a crucial antibody-binding site.

The hydrogen bond proton donor properties of volatile halogenated hydrocarbons and ethers and their mode of action in anaesthesia

A phase model previously used for estimating the anaesthetic potencies of halogenated hydrocarbons is briefly reviewed, and a hydrogen bond proton donor scale for the set of compounds has been refined. Two further effects of these compounds are examined, their lethal and cardiac sensitization effects. Comparison of lethal and anaesthetic concentrations supports the view that the volume of the anaesthetic within the cell membrane is a critical determinant of anaesthetic action. Differences in the contributory effects of hydrogen bonding to the lethal, anaesthetic, and cardiac sensitization potencies are observed. The influence of the hydrogen bond proton donor interaction of a partially halogenated hydrocarbon is some 30% greater in its anaesthetic action than in its lethal effect. Comparison of the lethal and cardiac sensitization potencies indicates a similar component difference in the influence of hydrogen bonding but of opposite effect. It is suggested that in addition to the colligative effects of the compounds the difference in the hydrogen bonding components may represent a common process of membrane desensitization. The process is reviewed in relation to existing concepts of membrane action.

Paraspecific neutralization of the venom of African species of cobra by an equine antiserum against Naja melanoleuca: A comparative study

Venoms of snakes belonging to the same Genera tend to share biochemical, toxinological and antigenic characteristics. Accordingly, paraspecific neutralization of venom lethality by experimental antisera and commercial antivenoms has been reported. We studied the spectrum of neutralization of lethality of an experimental monovalent equine antiserum against the strongly neurotoxic African forest cobra ( Naja melanoleuca) when tested against venoms of most species of African Naja, both neuro and cytotoxic as described by some authors. We report a comparison of the median lethal doses (LD 50) of the venoms and the paraspecific median effective doses (ED 50) of the antiserum calculated using three methods: Spearman–Kärber and Probit (currently recommended by the World Health Organization), and non-linear regression. An ample – but not complete – spectrum of paraspecific neutralization of lethality was observed against both spitting and non-spitting species of African Naja with a clearly more efficient neutralization of the more potent venoms, the implications of which are discussed. The median lethal and effective doses calculated by the three methods are remarkably consistent and may warrant consideration of non-linear regression methods for the calculation of venom lethality and antivenom potency by venom/antivenom researchers and producers.

Toxicity and Toxin Profiles of Xanthid Crabs Collected around Nakanoshima, the Tokara Islands, Japan

A total of 36 specimens of 5 xanthid crab species, Zosimus aeneus (n=16), Xanthias lividus (n=4), Leptodius sanguineus (n=3), Daira perlata (n=10) and Eriphia sebana (n=3), were collected around Nakanoshima Island, which is located at the northeastern part of the Tokara Islands, Kagoshima Prefecture, Japan in May and July 2000, and their toxicity was determined by mouse bioassay. Nine of 16 Z. aeneus specimens and all of 4 X. lividus specimens showed lethal potency to mice (2.1-11 MU/g, 2.8-8.6 MU/g, respectively), whereas all the other species were non-toxic (less than 2.0 MU/g). LC/MS analyses indicated that the toxin of the Z. aeneus specimens was mainly composed of tetrodotoxin (41% of total toxicity), and 11-oxotetrodotoxin contributed to the remaining toxicity. The toxin of the X. lividus specimens, however, was apparently not tetrodotoxin. In HPLC-FLD analyses, no paralytic shellfish poison component was detected in either of the two toxic species.

Acute Toxicity of Organophosphorus Compounds in Guinea Pigs Is Sex- and Age-Dependent and Cannot Be Solely Accounted for by Acetylcholinesterase Inhibition

This study was designed to test the hypothesis that the acute toxicity of the nerve agents S-[2-(diisopropylamino)ethyl]-O-ethyl methylphosphonothioate (VX), O-pinacolyl methylphosphonofluoridate (soman), and O-isopropyl methylphosphonofluoridate (sarin) in guinea pigs is age- and sex-dependent and cannot be fully accounted for by the irreversible inhibition of acetylcholinesterase (AChE). The subcutaneous doses of nerve agents needed to decrease 24-h survival of guinea pigs by 50% (LD(50) values) were estimated by probit analysis. In all animal groups, the rank order of LD(50) values was sarin > soman > VX. The LD(50) value of soman was not influenced by sex or age of the animals. In contrast, the LD(50) values of VX and sarin were lower in adult male than in age-matched female or younger guinea pigs. A colorimetric assay was used to determine the concentrations of nerve agents that inhibit in vitro 50% of AChE activity (IC(50) values) in guinea pig brain extracts, plasma, red blood cells, and whole blood. A positive correlation between LD(50) values and IC(50) values for AChE inhibition would support the hypothesis that AChE inhibition is a major determinant of the acute toxicity of the nerve agents. However, such a positive correlation was found only between LD(50) values and IC(50) values for AChE inhibition in brain extracts from neonatal and prepubertal guinea pigs. These results demonstrate for the first time that the lethal potencies of some nerve agents in guinea pigs are age- and sex-dependent. They also support the contention that mechanisms other than AChE inhibition contribute to the lethality of nerve agents.

A new venomous scorpion responsible for severe envenomation in Argentina: Tityus confluens

In Argentina the scorpions of medical importance belong to the genus Tityus ( T.), particularly the species T. trivittatus, the only scorpion whose sting is recognized to be associated with severe human envenoming and death. This genus is distributed from the north of the Patagonian region to the center and some provinces in the north of the country. During the period 2003–2006 four children died following scorpion stings, of which one was certainly and three were probably by T. confluens. In 2006, in the province of Tucumán, a girl died by scorpion envenoming and the scorpion responsible for the death, found in her shoe, was T. confluens. We thus studied the toxicity of venom gland homogenates from T. confluens from the provinces of Jujuy and Catamarca, and of crude venom from specimens from Catamarca and the province of La Rioja. The lethal potencies of the telson homogenates were 7.0 and 18.6 μg/g for Jujuy and Catamarca, respectively, while the lethal potency of the crude venom was 0.7 μg/g. Injected mice showed generalized congestion and hepatic lesions. Pancreatic damage was observed in some animals. Lungs showed congestion and foci of hemorrhage and mild edema. The heart showed injury in the muscular fibers. The venom showed high reactivity against anti- T. trivittatus antivenom and against two anti- T. serrulatus antivenoms. The anti- T. trivittatus antivenom neutralized the lethal activity of T. confluens venom. In addition, the venom reacted very slightly against an anti- Centruroides antivenom. Therefore, the stings of this scorpion must be considered of risk for humans to the same degree as the stings of T. trivittatus.

Acute toxicity of βγ-CAT, a naturally existing non-lens βγ-crystallin and trefoil factor complex from frog Bombina maxima skin secretions

In vertebrates, non-lens βγ-crystallins are widely expressed in various tissues, but their functions are unknown. The molecular mechanisms of trefoil factors, initiators of mucosal healing and being greatly involved in tumorigenesis, have remained elusive. βγ-CAT is the first example of a naturally existing multifunctional protein complex of a non-lens βγ-crystallin and a trefoil factor from frog Bombina maxima skin secretions. Here we report the investigation of its in vivo toxic effects on mice and rabbits. The LD 50 values of βγ-CAT on mice were determined to be 0.4 mg/kg and 20 μg/kg under intraperitoneal (i.p.) and intravenous (i.v.) injection, respectively. The mice subcutaneously injected with βγ-CAT (6 μg/g body weight) showed strong hyperaemia of subcutaneous capillary vessel, but no hemorrhagic spots were observed. Intravenous injection of βγ-CAT in rabbits (8–22 μg/kg body weight) caused a rapidly hypotensive effect and followed with cardiovascular collapse. Injection with βγ-CAT (22 μg/kg, i.v.) significantly decreased hematocrit ( P < 0.05) and mean corpuscular volume ( P < 0.05) of the rabbits in 5 min. At the same time, the counts of platelets and white blood cells were significantly decreased ( P < 0.05), while the blood levels of glucose, lactate dehydrogenase and serum glutamic–oxaloacetic transaminase were significantly increased ( P < 0.05). Furthermore, serials of tissues edema and damages were also observed. These results indicate that βγ-CAT rapidly caused several in vivo toxic effects on mammals and its lethal toxic potency was mainly contributed by hypotension and cardiovascular collapse, providing new clues for the understanding of the patho-physiological roles of non-lens βγ-crystallins and trefoil factors.

Restoration of Enzymatic Activity in a Ser-49 Phospholipase A2Homologue Decreases Its Ca2+-Independent Membrane-Damaging Activity and Increases Its Toxicity

Ammodytin L (AtnL) is a Ser-49 secretory phospholipase A2 (sPLA2) homologue with myotoxic activity. By analogy to the Lys-49 sPLA2 myotoxins, AtnL has been predicted to be enzymatically inactive due to the absence of the conserved Asp-49 that participates in coordination of the Ca2+ cofactor. By substituting Ser-49 and three other residues in the Ca2+-binding loop of AtnL, we obtained the first two enzymatically active mutants of Lys-49/Ser-49 sPLA2 homologues. The mutants LW and LV, which differed only by the presence of Trp and Val at position 31, respectively, efficiently hydrolyzed phospholipid vesicles, while recombinant AtnL displayed no activity. In contrast to AtnL but similarly to ammodytoxin A (AtxA), a homologous neurotoxic sPLA2, both mutants exhibited catalysis-dependent membrane-damaging ability, involving vesicle contents leakage and fusion. However, LW and LV also exhibited the potent, Ca2+-independent disruption of vesicle integrity characteristic of AtnL, but not of AtxA, in which leakage of the contents is not associated with membrane fusion. Although LV and, especially, LW have the advantage over AtnL of being able to act in both Ca2+-independent and Ca2+-dependent modes, and display higher cytotoxicity and higher lethal potency, they have a lower Ca2+-independent membrane-damaging potency and display reduced specificity in targeting muscle fibers in vitro. Our results indicate that, in evolution, Lys-49 and Ser-49 sPLA2 myotoxins have lost their Ca2+-binding ability and enzymatic activity through subtle changes in the Ca2+-binding network without affecting the rest of the catalytic machinery, thereby optimizing their Ca2+-independent membrane-damaging ability and myotoxic activity.

CARDIOTOXIN FROM TAIWAN COBRA (NAJA NAJA ATRA): STRUCTURE, DYNAMICS, INTERACTION AND PROTEIN FOLDING

Snake venom cardiotoxins, small molecular weight all β-sheet proteins, exhibit a broad spectrum of biological activities. The secondary structure elements in cardiotoxins include an antiparallel triple and a double stranded β-sheet. Basically, cardiotoxins are ‘three-finger’ shaped proteins with three loops projecting from a globular head. The three dimensional structures of these toxins reveal a unique asymmetric distribution of the hydrophobic and hydrophilic amino acids. Irrespective of 90% homology in the amino acid sequence that exists among these cardiotoxin isoforms, each differ in lethal potency. However, to date, there is no clear structure-function correlation(s) available for snake venom cardiotoxins. In this mini review, we provide an overview of our understanding and knowledge of the structure functional relationships of cardiotoxins from the Tawian cobra, Naja naja atra with critical evaluation on the recent progress in research on the structure, dynamics, interaction and folding aspects of snake cardiotoxins.

Comparative developmental toxicity of 2,3,7,8-tetrachlorodibenzo- p-dioxin in the hamster, rat and guinea pig

2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) is a persistent environmental contaminant capable of causing a wide variety of adverse health effects including teratogenesis and altered development. The objective of this study was to compare the developmental toxicity of TCDD in the hamster, rat and guinea pig, which in mature animals exhibit a relatively low, medium and high sensitivity to TCDD, respectively. A single oral dose of TCDD was administered to pregnant rats (0, 1.5, 3.0, 6.0 or 18.0 μg/kg) on gestation day 10, pregnant hamsters (0, 1.5, 3.0, 6.0 or 18.0 μg/kg) on gestation day 9 and pregnant guinea pigs (0, 0.15 or 1.5 μg/kg) on gestation day 14 with fetal analysis on gestation day 20, 15 and 56, respectively. The developmental toxicity of TCDD in the three species included increased fetal mortality, alterations to fetal body weight, body length, organ weight and significant changes to the fetal white blood cell differential counts. Additionally, teratogenic responses were observed in the hamster and rat consisting of cleft palate, kidney congestion, hydronephrosis and intestinal hemorrhaging. Furthermore, the results from this study demonstrate that despite the up to 5000-fold interspecies variability to the acute lethal potency of TCDD observed in mature guinea pigs, rats and hamsters, the developing fetus is uniquely vulnerable to gestational TCDD exposure and displays approximately a 10-fold variability in fetal lethal potency in these species. Together, these results will assist efforts to reduce the uncertainty in the risk assessment for TCDD in sensitive populations, such as the developing embryo and fetus.

Alcohol effects on embryonal bone growth

Background:The possible teratogenic and lethal potencies of ethanol on the developing foetal bones especially when ingested during pregnancy is now well established; but the actual mechanisms of these actions are yet elusive and this had since stimulated unending interests and numerous researches particularly in the field of teratology. Are there yet any other possible mediators / agents to be implicated in the potentiation of ethanol toxicity? Are they existing or would there be possible solutions for assaults of alcohol abuse? Methods: A retrospective and contemporary literature compilation was done in an attempt to further explore this subject and bring out more detailed information useful to answering these and other such lingering questions. Results: The incidence of congenital bone malformations associated with maternal consumption of ethanol during conception are now recognised to be due to its toxic effects on the developing tissues and impairment of normal cellular activities particularly by depriving them of essential vitamins such as folic acid, a useful precursor for the synthesis of proteins and DNA. Conclusion: This is a situation where the most successful preventive measures could possibly be instituted, with folic acid supplementation, to alleviate ethanol toxicity, if total abstinence is not possible. Nigerian Journal of Surgical Research Vol. 7(1&2) 2005: 152-158

Novel non-enzymatic toxic peptide of Daboia russelii (Eastern region) venom renders commercial polyvalent antivenom ineffective

The snake venoms are typically complex mixtures of enzymes and non-enzymatic peptides. Regional variation in the non-enzymatic fraction of Russell's viper venom from three regions of India studied. The eastern, western and southern regional venom upon gel permeation chromatography on sephadex-G-75 column resolved into three peaks. All the three overlapping peaks differ in their lethality and enzymatic potency. Peak III of all the regional venom found to be non-enzymatic, Western and southern regional venom has trypsin inhibitory activity with varying potencies. Interestingly, the peak III of eastern region is devoid of trypsin inhibitory activity. But it is highly lethal with a LD 50 0.7 mg/kg body weight and also it exhibited post-synaptic neurotoxicity. On the other hand southern and western regional venom's non-enzymatic peak is non-lethal and did not induce neurotoxic symptoms in experimental model. The antibodies developed against the eastern regional venom cross-reacted with the peaks I and II of other regional venom, but failed to cross-react with the peak III of western and southern regional Russell's viper venom. Commercial anti-venom prepared to neutralize the toxic effects of common poisonous snakes of India, showed positive cross-reaction against peaks I, II and III of all three regional venom tested, except peak III of eastern regional venom. Commercial anti-venom neutralized the lethal toxicity of both western and southern regional Russell's viper venom, and failed to neutralize the lethal effects of eastern regional Russell's viper venom.

Basic amino acid residues in the β-structure region contribute, but not critically, to presynaptic neurotoxicity of ammodytoxin A

The molecular mechanism of action of presynaptically toxic secreted phospholipases A 2 (sPLA 2s) isolated from snake venoms is not completely understood. It has been proposed that the positive charge in the β-structure region is important for their toxic activity. To test this hypothesis, we characterised several mutants of ammodytoxin A (AtxA) possessing substitution of all five basic residues in this region. The mutations had relatively little influence on the catalytic activity of AtxA, either on charge-neutral or anionic phospholipid vesicles. An exception was R72 when replaced by a hydrophobic (higher activity) or an acidic (lower activity) residue. Lethal potencies of the eight single site mutants were up to four times lower than that of the wild-type, whereas the triple mutant (K74S/H76S/R77L) was 13-fold less toxic. The substitutions also lowered the affinity of the toxin, slightly to moderately, for the neuronal receptors R25 and R180. Interaction with calmodulin was only slightly affected by substitutions of K86, more by those of the K74/H76/R77 cluster and most by those of R72 (up to 11-fold lower binding affinity). The results clearly indicate that the basic amino acid residues in the β-region of AtxA contribute to, but are not necessary for, its neurotoxic effect.

CONE CALORIMETER STUDIES ON FIRE BEHAVIOR OF POLYCARBONATE GLAZING SHEETS

Polycarbonate glazing sheets used to be protected by a film. Earlier fire investigations cases suspected ignition of polycarbonate is due to igniting the protective film. Therefore, polycarbonate materials with and without a protective coating were tested by a cone calorimeter under radiative heat fluxes of 10 kWm(sup)-2 to 70 kWm(sup)-2. In addition to thermal properties, smoke toxicity upon burning the materials was also studied. Values of lethal toxic potency LC(sub)50 deduced by measuring only carbon monoxide will be discussed. The calculation procedure with a cone calorimeter is clarified. It is found that polycarbonate would not be ignited under flashover heat flux at floor level of 20 kWm(sup)2. However, the sample would be ignited and then burned when there is a protective film. Smoke emitted will be more toxic in having lower value of LC(sub)50. Results confirmed that materials protected by the coating film might have a higher fire risk. Finally, a three-dimensional risk diagram with three parameters x, y, and z on flashover propensity, total heat released per unit area, and LC(sub)50 are proposed for hazard assessment. Language: en

Sublethal Effects of Fire Smoke

Fire smoke toxicity has been a recurring theme for fire safety professionals for over four decades. There especially continue to be difficulty and controversy in assessing and addressing the contribution of the sublethal effects of smoke in hazard and risk analyses. The Fire Protection Research Foundation (FPRF), the National Institute of Standards and Technology (NIST), and NFPA have begun a private/public fire research initiative, the “International Study of the Sublethal Effects of Fire Smoke on Survival and Health” (SEFS) to provide scientific information on these effects for public policy makers. The papers in this issue of Fire Technology present results from the first phase of the project: estimates of the magnitude and impact of sublethal exposures to fire smoke on the U.S. population, the best available lethal and incapacitating toxic potency values for the smoke from commercial products, the potential for various sizes of fires to produce smoke yields that could result in sublethal health effects, and state-of-the-art information on the production of the condensed components of smoke from fires and their evolutionary changes during transport from the fire.

Growing Old Disgracefully: The Cosmetic Use of Botulinum Toxin

The explosive growth in the use of botulinum toxin for cosmetic purposes has undoubtedly had an impact on the number of animals used in the potency testing of this product. The test used is a classical LD50, a severe procedure during which animals experience increasing paralysis until the occurrence of death. The enthusiastic adoption by the general public of the use of botulinum toxin as an anti-wrinkle treatment has, at least in Europe, paradoxically taken place against a background of moves to stop animal testing of cosmetics and cosmetic ingredients. There appears to be a dearth of information aimed at the public concerning botulinum toxin testing. Botulinum toxin does have important medical applications; however, the question arises whether a blanket licence for the testing can be justified, when a large proportion of the product is being used cosmetically. A further question is why death continues to be the endpoint of the potency test, when a more-humane endpoint has been proposed. In addition, a number of alternative methods have been developed, which could have the potential to replace the lethal potency test altogether. These methods are discussed in this paper, and the importance of establishing a strategy for their validation is emphasised, a need that has become even more urgent in the light of the recently published draft monograph on botulinum toxin by the European Pharmacopoeia Commission.