Liposomes are nanocarriers that deliver the payloads at the target site, leading to therapeutic drug concentrations at the diseased site and reduced toxic effects in healthy tissues. Several approaches have been used to enhance the ability of the nanocarrier to target the specific tissues, including ligand-targeted liposomes and stimuli-responsive liposomes. Ligand-targeted liposomes exhibit higher uptake by the target tissue due to the targeting ligand attached to the surface, while, the stimuli-responsive liposomes do not release their cargo unless they expose to an endogenous or exogenous stimulant at the target site. In this review, we mainly focus on the liposomes that are responsive to pathologically increased levels of enzymes at the target site. Enzyme-responsive liposomes release their cargo upon contact with the enzyme through several destabilization mechanisms: a) structural perturbation in the lipid bilayer, b) removal of a shielding polymer from the surface and increased cellular uptake, c) cleavage of a lipopeptide or lipopolymer incorporated in the bilayer, and d) activation of a prodrug in the liposomes.
Hand sanitizers are effective and inexpensive products that can reduce microorganisms on the skin, but ingestion or improper use can be associated with health risks. Many hand sanitizers contain up to 60%-95% ethanol or isopropyl alcohol by volume, and are often combined with scents that might be appealing to young children. Recent reports have identified serious consequences, including apnea, acidosis, and coma in young children who swallowed alcohol-based (alcohol) hand sanitizer (1-3). Poison control centers collect data on intentional and unintentional exposures to hand sanitizer solutions resulting from various routes of exposure, including ingestion, inhalation, and dermal and ocular exposures. To characterize exposures of children aged ≤12 years to alcohol hand sanitizers, CDC analyzed data reported to the National Poison Data System (NPDS).* The major route of exposure to both alcohol and nonalcohol-based (nonalcohol) hand sanitizers was ingestion. The majority of intentional exposures to alcohol hand sanitizers occurred in children aged 6-12 years. Alcohol hand sanitizer exposures were associated with worse outcomes than were nonalcohol hand sanitizer exposures. Caregivers and health care providers should be aware of the potential dangers associated with hand sanitizer ingestion. Children using alcohol hand sanitizers should be supervised and these products should be kept out of reach from children when not in use.
The quality of diets in rodent feeding trials is crucial. We describe the contamination with environmental pollutants of 13 laboratory rodent diets from 5 continents. Measurements were performed using accredited methodologies. All diets were contaminated with pesticides (1-6 out of 262 measured), heavy metals (2-3 out of 4, mostly lead and cadmium), PCDD/Fs (1-13 out of 17) and PCBs (5-15 out of 18). Out of 22 GMOs tested for, Roundup-tolerant GMOs were the most frequently detected, constituting up to 48% of the diet. The main pesticide detected was Roundup, with residues of glyphosate and AMPA in 9 of the 13 diets, up to 370 ppb. The levels correlated with the amount of Roundup-tolerant GMOs. Toxic effects of these pollutants on liver, neurodevelopment, and reproduction are documented. The sum of the hazard quotients of the pollutants in the diets (an estimator of risk with a threshold of 1) varied from 15.8 to 40.5. Thus the chronic consumption of these diets can be considered at risk. Efforts toward safer diets will improve the reliability of toxicity tests in biomedical research and regulatory toxicology.
Venomous animals have toxins associated with delivery mechanisms that can introduce the toxins into another animal . Although most amphibian species produce or sequester noxious or toxic secretions in the granular glands of the skin to use as antipredator mechanisms [2, 3], amphibians have been considered poisonous rather than venomous because delivery mechanisms are absent. The skin secretions of two Brazilian hylid frogs (Corythomantis greeningi  and Aparasphenodon brunoi) are more toxic than the venoms of deadly venomous Brazilian pitvipers, genus Bothrops ; C. greeningi secretion is 2-fold and A. brunoi secretion is 25-fold as lethal as Bothrops venom. Like the venoms of other animals, the skin secretions of these frogs show proteolytic and fibrinolytic activity and have hyaluronidase, which is nontoxic and nonproteolytic but promotes diffusion of toxins. These frogs have well-developed delivery mechanisms, utilizing bony spines on the skull that pierce the skin in areas with concentrations of skin glands. C. greeningi has greater development of head spines and enlarged skin glands producing a greater volume of secretion, while A. brunoi has more lethal venom. C. greeningi and A. brunoi have highly toxic skin secretions and an associated delivery mechanism; they are therefore venomous. Because even tiny amounts of these secretions introduced into a wound caused by the head spines could be dangerous, these frogs are capable of using their skin toxins as venoms against would-be predators.
Pesticides are a collective term for a wide array of chemicals intended to kill unwanted insects, plants, molds, and rodents. Food, water, and treatment in the home, yard, and school are all potential sources of children’s exposure. Exposures to pesticides may be overt or subacute, and effects range from acute to chronic toxicity. In 2008, pesticides were the ninth most common substance reported to poison control centers, and approximately 45% of all reports of pesticide poisoning were for children. Organophosphate and carbamate poisoning are perhaps the most widely known acute poisoning syndromes, can be diagnosed by depressed red blood cell cholinesterase levels, and have available antidotal therapy. However, numerous other pesticides that may cause acute toxicity, such as pyrethroid and neonicotinoid insecticides, herbicides, fungicides, and rodenticides, also have specific toxic effects; recognition of these effects may help identify acute exposures. Evidence is increasingly emerging about chronic health implications from both acute and chronic exposure. A growing body of epidemiological evidence demonstrates associations between parental use of pesticides, particularly insecticides, with acute lymphocytic leukemia and brain tumors. Prenatal, household, and occupational exposures (maternal and paternal) appear to be the largest risks. Prospective cohort studies link early-life exposure to organophosphates and organochlorine pesticides (primarily DDT) with adverse effects on neurodevelopment and behavior. Among the findings associated with increased pesticide levels are poorer mental development by using the Bayley index and increased scores on measures assessing pervasive developmental disorder, inattention, and attention-deficit/hyperactivity disorder. Related animal toxicology studies provide supportive biological plausibility for these findings. Additional data suggest that there may also be an association between parental pesticide use and adverse birth outcomes including physical birth defects, low birth weight, and fetal death, although the data are less robust than for cancer and neurodevelopmental effects. Children’s exposures to pesticides should be limited as much as possible.
Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels
- International journal of environmental research and public health
- Published over 1 year ago
Pesticide formulations contain declared active ingredients and co-formulants presented as inert and confidential compounds. We tested the endocrine disruption of co-formulants in six glyphosate-based herbicides (GBH), the most used pesticides worldwide. All co-formulants and formulations were comparably cytotoxic well below the agricultural dilution of 1% (18-2000 times for co-formulants, 8-141 times for formulations), and not the declared active ingredient glyphosate (G) alone. The endocrine-disrupting effects of all these compounds were measured on aromatase activity, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was decreased both by the co-formulants alone (polyethoxylated tallow amine-POEA and alkyl polyglucoside-APG) and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G exerted an effect only at 1/3 of the agricultural dilution. It was demonstrated for the first time that endocrine disruption by GBH could not only be due to the declared active ingredient but also to co-formulants. These results could explain numerous in vivo results with GBHs not seen with G alone; moreover, they challenge the relevance of the acceptable daily intake (ADI) value for GBHs exposures, currently calculated from toxicity tests of the declared active ingredient alone.
Since laser treatment of tattoos is the favored method for the removing of no longer wanted permanent skin paintings, analytical, biokinetics and toxicological data on the fragmentation pattern of commonly used pigments are urgently required for health safety reasons. Applying dynamic headspace-gas chromatography with mass spectrometric detection (DHS-GC/MS) and comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GCxGC-ToF-MS), we identified 1,2-benzene dicarbonitrile, benzonitrile, benzene, and the poisonous gas hydrogen cyanide (HCN) as main fragmentation products emerging dose-dependently upon ruby laser irradiation of the popular blue pigment copper phthalocyanine in suspension. Skin cell viability was found to be significantly compromised at cyanide levels of ≥1 mM liberated during ruby laser irradiation of >1.5 mg/ml phthalocyanine blue. Further, for the first time we introduce pyrolysis-GC/MS as method suitable to simulate pigment fragmentation that may occur spontaneously or during laser removal of organic pigments in the living skin of tattooed people. According to the literature such regular tattoos hold up to 9 mg pigment/cm(2) skin.
- Toxicon : official journal of the International Society on Toxinology
- Published about 5 years ago
Phospholipases A(2) (PLA(2)s) are abundant components of snake venoms, where they play toxic and digestive roles. Despite having a similar three-dimensional structure, venom PLA(2)s exert an amazing variety of toxic and pharmacological effects, which include neurotoxic, myotoxic, hemolytic, edematogenic, hyperalgesic, pro-inflammatory, hypotensive, platelet-aggregation inhibitory, anticoagulant, cytotoxic, and bactericidal activities. Toxinologists have made significant contributions to deciphering the structure, molecular evolution, mechanisms of action, receptors, role of enzymatic activity for toxicity, structural determinants of toxicity and selectivity, and the impact of these enzymes in the overall pathophysiology of snakebite envenoming. The present work highlights some of the most relevant contributions in the study of venom PLA(2)s, including the personal accounts of the authors of these studies.
Here we report the case of a 70-year-old woman who committed suicide by cyanide poisoning. During resuscitation cares, she underwent an antidote treatment by hydroxocobalamin. Postmortem investigations showed marked bright pink discolouration of organs and fluids, and a lethal cyanide blood concentration of 43mg/L was detected by toxicological investigation. Discolouration of hypostasis and organs has widely been studied in forensic literature. In our case, we interpreted the unusual pink coloration as the result of the presence of hydroxocobalamin. This substance is a known antidote against cyanide poisoning, indicated because of its efficiency and poor adverse effects. However, its main drawback is to interfere with measurements of many routine biochemical parameters. We have tested the potential influence of this molecule in some routine postmortem investigations. The results are discussed.
PSP toxin release from the cyanobacterium Raphidiopsis brookii D9 (Nostocales) can be induced by sodium and potassium ions.
- Toxicon : official journal of the International Society on Toxinology
- Published about 5 years ago
Paralytic shellfish poisoning (PSP) toxins are a group of naturally occurring neurotoxic alkaloids produced among several genera of primarily freshwater cyanobacteria and marine dinoflagellates. Although saxitoxin (STX) and analogs are all potent Na(+) channel blockers in vertebrate cells, the functional role of these compounds for the toxigenic microorganisms is unknown. Based upon the known importance of monovalent cations (such as sodium) in the maintenance of cellular homeostasis and ion channel function, we examined the effect of high extracellular concentrations of these ions on growth, cellular integrity, toxin production and release to the external medium in the filamentous freshwater cyanobacterium, Raphidiopsis brookii D9; a gonyautoxins (GTX2/3) and STX producing toxigenic strain. We observed a toxin export in response to high (17 mM) NaCl and KCl concentrations in the growth medium that was not primarily related to osmotic stress effects, compared to the osmolyte mannitol. Addition of exogenous PSP toxins with the same compositional profile as the one produced by R. brookii D9 was able to partially mitigate this effect of high Na(+) (17 mM). The PSP toxin biosynthetic gene cluster (sxt) in D9 has two genes (sxtF and sxtM) that encode for a MATE (multidrug and toxic compound extrusion) transporter. This protein family, represented by NorM in the bacterium Vibrio parahaemolyticus, confers resistance to multiple cationic toxic agents through Na(+)/drug antiporters. Conserved domains for Na(+) and drug recognition have been described in NorM. For the D9 sxt cluster, the Na(+) recognition domain is conserved in both SxtF and SxtM, but the drug recognition domain differs between them. These results suggest that PSP toxins are exported directly in response to the presence of monovalent cations (Na(+), K(+)) at least at elevated concentrations. Thus, the presence of both genes in the sxt cluster from strain D9 can be explained as a selective recognition mechanism by the SxtF/M transporters for GTX2/3 and STX. We propose that these toxins in cyanobacteria could act extracellularly as a protective mechanism to ensure homeostasis against extreme salt variation in the environment.