Differential Cytotoxicity of Haloaromatic Disinfection Byproducts and Lead Co-exposures against Human Intestinal and Neuronal Cells.

Disinfecting drinking water with chlorine inadvertently generates disinfection byproducts (DBPs) which can cause potential adverse health effects to humans. Haloaromatic DBPs are a group of emerging DBPs recently identified, suspected to be substantially more toxic than haloaliphatic DBPs but have not been extensively studied. Simultaneously, service pipelines made of lead materials are widely used in water distribution systems and become a source of dissolved lead (Pb) in tap water. In this study, we investigated the cytotoxicity of nine haloaromatic DBPs and lead ion (Pb2+), both separately as well as in combination, to human epithelial colorectal adenocarcinoma (Caco-2) and neuroblastoma (SH-SY5Y) cells. Results show that the cytotoxicity of the DBPs against Caco-2 cells followed the descending rank order of 2,4,6-triiodophenol ≅ 2,5-dibromohydroquinone > 2,4,6-tribromophenol > 3,5-dibromo-4-hydroxybenzaldehyde ≅ 2,4,6-trichlorophenol > 4-chlorophenol ≅ 3,5-dibromo-4-hydroxybenzoic acid > 2,6-dichlorophenol >5-chlorosalicylic acid, and the cytotoxicity of the DBPs against SH-SY5Y cells followed a similar rank order, 2,4,6-triiodophenol ≅ 2,5-dibromohydroquinone > 2,4,6-tribromophenol > 3,5-dibromo-4-hydroxybenzaldehyde ≅ 2,4,6-trichlorophenol > 4-chlorophenol > 3,5-dibromo-4-hydroxybenzoic acid > 2,6-dichlorophenol ≅ 5-chlorosalicylic acid. Lead in water did not change the toxicity of 3,5-dibromo-4-hydroxybenzoic acid (to either cell-type) or the toxicity of 4-chlorophenol (to the neuronal cell-type); but Pb2+ exhibited different degrees of synergistic effects with other tested DBPs. The synergism resulted in different rank orders of cytotoxicity against both intestinal and neuronal cells. These data indicate that future prioritization and regulation of emerging haloaromatic DBPs in drinking water should be considered in terms of their own toxicity and combinatorial effects with lead in water.

Initial hazard assessment of 1,4-dichlorobutane: Genotoxicity tests, 28-day repeated-dose toxicity test, and reproductive/developmental toxicity screening test in rats.

1,4-Dichlorobutane (1,4-DCB) is used as raw materials for drugs, pesticides, fragrances, and chemical fibers, and being used as a solvent. Its toxicity data was insufficient for screening assessment under the Japanese Chemical Substances Control Law. We conducted toxicity tests and hazard classification for screening assessment 1,4-DCB showed negative in the Ames test, positive in the in vitro chromosomal aberrations test with metabolic activation, and negative in the in vivo mouse bone-marrow micronucleus test. The 28-day repeated-dose toxicity study, where male and female rats were administered 1,4-DCB by gavage at 0, 12, 60, and 300 mg/kg/day, showed significant effects on the liver and pancreas from 12 mg/kg/day and kidney at 300 mg/kg/day. Based on periportal hepatocellular hypertrophy and decreased zymogen granules in pancreas, the lowest observed adverse effect level (LOAEL) of 12 mg/kg/day was obtained. The reproductive/developmental toxicity screening study, in which male and female rats were administered 1,4-DCB by gavage at dose of 0, 2.4, 12, and 60 mg/kg/day for 42-46 days, showed that the delivery index was decreased at 60 mg/kg/day without maternal toxicity. Based on the general toxicity, we classified this chemical as hazard class 2, with a D-value (Derived No Effect Level) of 0.002 mg/kg/day.

Computer and electronic duster spray inhalation (huffing) injuries managed at emergency departments.

Background: Computer and electronic duster sprays contain halogenated hydrocarbon gases. Intentional inhalation of computer and electronic duster sprays to induce intoxication, also known as huffing, may cause serious adverse effects and even death.Objectives: Describe computer and electronic duster spray inhalation-related injuries managed at United States (US) emergency departments (EDs).Methods: Data were obtained from the National Electronic Injury Surveillance System (NEISS), a database of consumer product-related injuries collected from the EDs of approximately 100 hospitals in the US. Cases were computer and electronic duster spray inhalation-related injuries included in NEISS during 2001-2017. The distribution by selected variables was determined for the resulting cases as well as a weighted estimate.Results: A total of 320 computer and electronic duster spray inhalation-related injuries were identified, resulting in a national estimate of 14,715 (95% confidence interval 11,120-18,311) such injuries. The annual estimated number of injuries remained low during 2001-2008 then increased during 2008-2017. Of the estimated injury patients, 3.2% were aged 6-12 years, 20.3% 13-19 years, and 76.5% 20-59 years; 65.4% of the patients were male. The disposition of the patient was 71.4% treated and examined and released, 6.9% treated and transferred, 11.6% treated and admitted or hospitalized, 0.7% held for observation, and 8.7% left without being seen.Conclusion: This study suggests that computer and electronic duster spray inhalation (huffing) may be an increasing issue of which hospital EDs and other clinicians should be aware. The pattern of injuries observed may be useful for targeting education, prevention and management activities.

Bromochloromethane, a Methane Analogue, Affects the Microbiota and Metabolic Profiles of the Rat Gastrointestinal Tract.

Bromochloromethane (BCM), an inhibitor of methanogenesis, has been used in animal production. However, little is known about its impact on the intestinal microbiota and metabolic patterns. The present study aimed to investigate the effect of BCM on the colonic bacterial community and metabolism by establishing a Wistar rat model. Twenty male Wistar rats were randomly divided into two groups (control and treated with BCM) and raised for 6 weeks. Bacterial fermentation products in the cecum were determined, and colonic methanogens and sulfate-reducing bacteria (SRB) were quantified. The colonic microbiota was analyzed by pyrosequencing of the 16S rRNA genes, and metabolites were profiled by gas chromatography and mass spectrometry. The results showed that BCM did not affect body weight and feed intake, but it did significantly change the intestinal metabolic profiles. Cecal protein fermentation was enhanced by BCM, as methylamine, putrescine, phenylethylamine, tyramine, and skatole were significantly increased. Colonic fatty acid and carbohydrate concentrations were significantly decreased, indicating the perturbation of lipid and carbohydrate metabolism by BCM. BCM treatment decreased the abundance of methanogen populations, while SRB were increased in the colon. BCM did not affect the total colonic bacterial counts but significantly altered the bacterial community composition by decreasing the abundance of actinobacteria, acidobacteria, and proteobacteria. The results demonstrated that BCM treatment significantly altered the microbiotic and metabolite profiles in the intestines, which may provide further information on the use of BCM in animal production.

An antimethanogenic nutritional intervention in early life of ruminants modifies ruminal colonization by Archaea.

The aim of this work was to study whether feeding a methanogen inhibitor from birth of goat kids and their does has an impact on the archaeal population colonizing the rumen and to what extent the impact persists later in life. Sixteen goats giving birth to two kids were used. Eight does were treated (D+) with bromochloromethane after giving birth and over 2 months. The other 8 goats were not treated (D-). One kid per doe in both groups was treated with bromochloromethane (k+) for 3 months while the other was untreated (k-), resulting in four experimental groups: D+/k+, D+/k-, D-/k+, and D-/k-. Rumen samples were collected from kids at weaning and 1 and 4 months after (3 and 6 months after birth) and from does at the end of the treating period (2 months). Pyrosequencing analyses showed a modified archaeal community composition colonizing the rumen of kids, although such effect did not persist entirely 4 months after; however, some less abundant groups remained different in treated and control animals. The different response on the archaeal community composition observed between offspring and adult goats suggests that the competition occurring in the developing rumen to occupy different niches offer potential for intervention.

Reevaluation of the Munro dataset to derive more specific TTC thresholds.

The threshold of toxicological concern (TTC) concept is a risk assessment tool for substances present at low oral exposure and lacking hazard data. In the past, several thresholds were elaborated by Munro et al. (1996) and Kroes et al. (2004). For these TTC thresholds, the Cramer class III threshold is based on a broad spectrum of substances, including organophosphates. For organophosphates a separate threshold was elaborated by Kroes et al. (2004), however without adjustment of the Cramer class III threshold. Moreover, reference was made by Munro et al. (2008) that for organohalogens a separate threshold also may apply whereas the EFSA (2012) considers that carbamate substances with anti-choline esterase activity can be included in the threshold for organophosphates. In this paper, a reevaluation of the Munro dataset (original TTC database) was performed, focused on the thresholds for organophosphates including carbamates, organohalogens and remaining Cramer class III substances. This way thresholds for each of these groups are elaborated. As a results of the current reevaluation of the Munro dataset, thresholds for life-time exposure are elaborated for the group of organophosphates including carbamates, the group of organohalogens and the remaining Cramer class III substances, being 0.30, 1.5 and 4.0 µg/kg bodyweight/day, respectively.

A phase I dose escalation study of TTI-237 in patients with advanced malignant solid tumors.

PURPOSE: This study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of TTI-237, a novel anti-tubulin drug, administered weekly in patients with refractory solid tumors. PATIENTS AND METHODS: Using an accelerated dose escalation design, patients with refractory solid tumors were enrolled in this study and treated with TTI-237 intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose was 4.5 mg/m(2). Pharmacokinetic studies were performed in patients at all dose levels. RESULT: Twenty-eight patients were enrolled and treated with TTI-237 at dose of 4.5, 9, 15, 22.5 and 31.5 mg/m(2). One dose-limiting toxicity neutropenia fever was observed at 31.5 mg/m(2), and all seven patients developed grade 3 or 4 neutropenia at that dose level. TTI-237 dosage was de-escalated to 22.5 and 18 mg/m(2). Six patients were treated at the 18 mg/m(2) dose level without dose-limiting toxicity prior to trial termination. The mean terminal-phase elimination half-life (t(1/2)) for TTI-237 was 25-29 h, and the mean area under the concentration time curve at 31.5 mg/m(2) was 2,768 ng•h/mL. CONCLUSION: A protocol defined maximum tolerated dose was not determined because of early termination of the TTI-237 trial by the sponsor. 18 mg/m(2) may be a tolerable dose of TTI-237.

Effect of bromochloromethane on methane emission, rumen fermentation pattern, milk yield, and fatty acid profile in lactating dairy goats.

Several technologies have been tested to reduce enteric methanogenesis, but very few have been successfully used in practical conditions for livestock. Furthermore, the consequences of reduced rumen methane production on animal performance and milk quality are poorly understood. The aim of this work was to investigate the effect of feeding bromochloromethane (BCM), a halogenated aliphatic hydrocarbon with potential antimethanogenic activity, to dairy goats on rumen methane production, fermentation pattern, the abundance of major microbial groups, and on animal performance and milk composition. Eighteen goats were allocated to 2 experimental groups of 9 animals each: treated (BCM+) or not (BCM-) with 0.30 g of BCM/100 kg of body weight per day. The BCM was administered per os in 2 equal doses per day from parturition to 2 wk postweaning (10 wk). After weaning, methane emissions were recorded over 2 consecutive days (d 57 and 58 on treatment) in polycarbonate chambers. On d 59, individual rumen fluid samples were collected for volatile fatty acid (VFA) analysis and quantification of bacterial, protozoal, and archaeal numbers by real-time PCR. On d 69 and 70, daily milk production was recorded and samples were collected for determination of fat, protein, lactose, casein, and total solids concentration by infrared spectrophotometry, and fatty acid composition by gas chromatography. Treatment with BCM reduced methane production by 33% (21.6 vs. 14.4 L/kg of DMI) compared with nontreated animals, although it did not affect the abundance of rumen bacteria, protozoa, and total methanogenic archaea. The observed improvement in the efficiency of digestive processes was accompanied by a 36% increase in milk yield, probably due to the more propionic type of rumen fermentation and an increase in VFA production. The increase in milk yield was not accompanied by any changes in the concentrations or yields of fat, protein, or lactose. Despite the substantial decrease in methane production, only minor changes in milk fatty acid profile were observed, suggesting that ruminal biohydrogenation pathways were not affected. Compounds that influence terminal biochemical pathways for methane production deserve further development for future application in the dairy goat sector.

Optimal design for the precise estimation of an interaction threshold: the impact of exposure to a mixture of 18 polyhalogenated aromatic hydrocarbons.

Traditional additivity models provide little flexibility in modeling the dose-response relationships of the single agents in a mixture. While the flexible single chemical required (FSCR) methods allow greater flexibility, its implicit nature is an obstacle in the formation of the parameter covariance matrix, which forms the basis for many statistical optimality design criteria. The goal of this effort is to develop a method for constructing the parameter covariance matrix for the FSCR models, so that (local) alphabetic optimality criteria can be applied. Data from Crofton et al. are provided as motivation; in an experiment designed to determine the effect of 18 polyhalogenated aromatic hydrocarbons on serum total thyroxine (T(4)), the interaction among the chemicals was statistically significant. Gennings et al. fit the FSCR interaction threshold model to the data. The resulting estimate of the interaction threshold was positive and within the observed dose region, providing evidence of a dose-dependent interaction. However, the corresponding likelihood-ratio-based confidence interval was wide and included zero. In order to more precisely estimate the location of the interaction threshold, supplemental data are required. Using the available data as the first stage, the Ds-optimal second-stage design criterion was applied to minimize the variance of the hypothesized interaction threshold. Practical concerns associated with the resulting design are discussed and addressed using the penalized optimality criterion. Results demonstrate that the penalized Ds-optimal second-stage design can be used to more precisely define the interaction threshold while maintaining the characteristics deemed important in practice.

Inhalation of computer duster spray among adolescents: an emerging public health threat?

BACKGROUND: Anecdotal reports and recent medical examiner and poison control center studies suggest that computer duster spray (CDS) inhalation is an emerging public health threat. However, there is a current dearth of empirical data on CDS use. OBJECTIVES: Study aims were to examine the prevalence, frequency, correlates, and modalities of CDS use among a treatment sample of antisocial youth. METHODS: A battery of standardized psychosocial instruments was administered via interview of 723 Missouri adolescents in residential care for antisocial behavior. RESULTS: Lifetime CDS use was prevalent (14.7%) in this young service population (97.7% of whom participated). CDS users were significantly more likely to report histories of perinatal injuries or illness, traumatic experiences, suicidality and physician-diagnosed mental illness, and evidenced higher levels of psychiatric symptoms, antisocial attitudes and behaviors, and polydrug use than CDS nonusers. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: CDS use was endemic in this treatment sample of adolescents and associated with a range of clinically significant comorbidities. Current findings describe an underrecognized and potentially dangerous form of substance misuse that has rarely been studied but that may be of growing importance.

Rapid elimination of field colonies of subterranean termites (Isoptera: Rhinotermitidae) using bistrifluron solid bait pellets.

The efficacy of bistrifluron, a chitin synthesis inhibitor, in cellulose bait pellets was evaluated on the mound-building subterranean termite, Coptotermes acinaciformis (Froggatt). Three concentrations of the bistrifluron were used: 0 (untreated control), 0.5, and 1.0% over an 8 wk period. Both doses of bistrifluron bait eliminated (viz. termites absent from nest or mound) termite colonies: 83% of colonies (10 of 12) were either eliminated or moribund (viz. colony had no reproductive capacity and decreased workforce) after 8 wk, compared with none of the control colonies. The remaining two treated colonies were deemed to be in decline. Early signs that bistrifluron was affecting the colonies included: 3 wk after baiting mound temperatures showed a loss of metabolic heat, 4 wk after baiting foraging activity in feeding stations was reduced or absent, and dissection of two mounds at 4 wk showed they were moribund. Colony elimination was achieved in around half or less the time, and with less bait toxicant, than other bait products tested under similar conditions in the field, because of either the active ingredient, the high surface area of the pellets, or a combination of both. This suggests the sometimes long times reported for control using baits may be reduced significantly. The use of a mound building species demonstrated clearly colony level effects before and after termites stopped foraging in bait stations.

Pharmacokinetics and Tolerability of LC28-0126, a Novel Necrosis Inhibitor, After Multiple Ascending Doses: A Phase I Randomized, Double-blind, Placebo-controlled Study in Healthy Male Subjects.

PURPOSE: LC28-0126 is a reactive oxygen species scavenger being developed for the treatment of various conditions caused by oxidative stress, such as oral mucositis, graft-versus-host disease, and lethal reperfusion injury in acute myocardial infarction. The aim of this study was to assess the tolerability and pharmacokinetic properties of LC28-0126 with multiple IV administrations in healthy male subjects. METHODS: A dose-block-randomized, double-blind, placebo-controlled, multiple ascending-dose study was conducted. Subjects received 3-, 10-, 20-, or 30-mg doses of LC28-0126 or inactive control vehicle, infused over 30 min, once daily for 7 days. Blood and urine samples were collected for pharmacokinetics assessment. Tolerability was assessed by the documentation of adverse events, including abnormal findings on physical examination, vital sign measurements, blood oxygen saturation monitoring, 12-lead ECG, continuous ECG monitoring, and clinical laboratory testing. FINDINGS: A total of 32 subjects completed the study. After multiple dosing, the plasma concentration of LC28-0126 showed a steep decrease after infusion, followed by slow elimination. Systemic exposure of LC28-0126 was increased proportionally to doses ranging from 3 to 30 mg. The accumulation ratios were 2.58-2.79 on multiple dosing. The fractions excreted unchanged in urine were found to be <5%. All reported drug-related adverse events were injection-site reactions, and no serious adverse events were reported. IMPLICATIONS: Multiple administrations of LC28-0126 exhibited a dose-proportional pharmacokinetic profile and were well tolerated at a dose range of 3-30 mg. ClinicalTrials.gov identifier: NCT03196804.

Polychlorinated biphenyl- and triphenyl-induced gastric mucosal hyperplasia in primates.

Polychlorinated biphenyl or triphenyl ingestion by subhuman primates for 3 months produced hyperplasia and dysplasia of the gastric mucosa. The concentration of the biphenyl within the experimental diet was less than an order of magnitude greater than that occurring in random food samples sold in the United States and less than levels which have occurred in food products as a result of industrial accidents. The increased cellularity, abnormal dysplastic growth pattern, and invasion of the adjacent tissue region indicate compromised gastric function and are suggestive of an eventual neoplastic transformation.

2,3,7,8-Tetrachlorodibenzo-p-dioxin: a potent inducer of -aminolevulinic acid synthetase.

2,3,7,8-Tetrachlorodibenzo-p-dioxin, a toxic contaminant frequently formed during the synthesis of the herbicide 2,4,5-trichlorophenoxyacetic acid, was shown to be a potent inducer of hepatic delta-aminolevulinic acid synthetase in the chick embryo. As little as 4.66 x 10(-12) mole of the contaminant per egg produces a significant increase in the activity of the enzyme. Induction of the enzyme is related to the dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin and, in contrast to that produced with other drugs, is prolonged in time, with 70 percent of the maximum induced activity present 5 days after a single dose. This contaminant is implicated as the likely causative agent in an outbreak of porphyria cutanea tarda in workers in a factory where 2,4,5-trichlorophenoxyacetic acid was being synthesized.

Inhalant abuse: a case of hemoptysis associated with halogenated hydrocarbons abuse.

An 18-year-old man presented to a community emergency department with increasing shortness of breath and fever. His condition was diagnosed, and he was treated as an inpatient for bilateral pneumonia associated with hypoxemia. When his condition became worse, he acknowledged to deliberate inhalation of keyboard cleaner and to having hemoptysis. Before his death on hospital day 11, known causes of alveolar hemorrhage were excluded. We postulated a cause-and-effect relationship, adding alveolar hemorrhage to the known complications of inhalant abuse.

Halogenated Agents and Cardiovascular Surgery: Has Mortality Really Decreased?

Halogenated anesthetic agents (desflurane, isoflurane and sevoflurane) may have cardioprotective properties at therapeutic doses against myocardial intraoperative ischemia-reperfusion injury. Cardioprotection mechanisms are related to mitochondrial and anti-apoptotic signaling pathways. Experimentals and human studies have proven that their use may reduce morbidity and mortality in the setting of cardiac surgery, including a reduction in myocardial infarct size and mechanical ventilation needs. In contrast, total intra-venous propofol based anesthesia may be detrimental. In the present review, we show the rationale for the perioperative use of halogenated anesthetics based on mechanisms of action, experimental research and human studies. Considerations and major concerns regarding their use, the present evidence for their use in other areas, such as major non-cardiac surgery and intensive care unit patients, and future perspectives are also discussed.

Mechanisms of Cardioprotection of Halogenated Agents During Extracorporeal Circulation in Cardiac Surgery.

The implementation of cardioprotective strategies involving pre-, intra-, and postoperative interventions is key during cardiac surgery requiring extracorporeal circulation (ECC). The primary goal of this study was to review the physiopathology and protection strategies against myocardial damage secondary to ECC during cardiac surgery. The administration halogenated anesthetics for cardiac anesthesia is common place due to their well-known cardioprotective effects and their capacity to ensure hypnosis. An optimal myocardial protection strategy requires that a comprehensive approach should be adopted to cover pre-, intra-, and post-operative interventions. Pre-conditioning and post-conditioning share numerous pathways, mainly based on mitochondrial signaling, antiapoptotic pathways, and reduced inflammatory mediators. However, volatile anesthetic can also be administered during ECC, in which mechanism of action has been scantly investigated, during this period and its biology is still unknown.

Ventricular arrhythmias induced in monkeys by the inhalation of aerosol propellants.

After inhaling fluoroalkane gases, which are used as aerosol propellants, some people have died suddently and unexpectedly. Seeking an explanation, we had 14 monkeys inhale these gases. All developed ventricular premature beats, bigeminy, or tachycardia, which began at an average of 39 (SE +/-4.2) sec. Fluoroalkanes were present in blood, but arterial hypoxemia or hypercapnia was absent, and arterial pressure was reduced only slightly. In contrast, without fluoroalkanes, 3 min of asphyxia or anoxia caused arrhythmias in only one monkey whose arterial oxygen tension had fallen to 16 mm Hg. The ventricular arrhythmias caused in well oxygenated monkeys by fluoroalkane gases may either be mediated through beta adrenergic receptors, since propranolol abolished these arrhythmias, or result from a nonadrenergic, direct, toxic effect of these gases on the heart. These results suggest that some deaths after propellant inhalation may be caused by ventricular tachycardia or fibrillation.

Induction of apoptosis using inhibitors of lysophosphatidic acid acyltransferase-beta and anti-CD20 monoclonal antibodies for treatment of human non-Hodgkin's lymphomas.

PURPOSE: Lysophosphatidic acid acyltransferase-beta (LPAAT-beta) is a transmembrane enzyme critical for the biosynthesis of phosphoglycerides whose product, phosphatidic acid, plays a key role in raf and AKT/mTor-mediated signal transduction. EXPERIMENTAL DESIGN: LPAAT-beta may be a novel target for anticancer therapy, and, thus, we examined the effects of a series of inhibitors of LPAAT-beta on multiple human non-Hodgkin's lymphoma cell lines in vitro and in vivo. RESULTS: We showed that five LPAAT-beta inhibitors at doses of 500 nmol/L routinely inhibited growth in a panel of human lymphoma cell lines in vitro by >90%, as measured by [3H]thymidine incorporation. Apoptotic effects of the LPAAT-beta inhibitors were evaluated either alone or in combination with the anti-CD20 antibody, Rituximab. The LPAAT-beta inhibitors induced caspase-mediated apoptosis at 50 to 100 nmol/L in up to 90% of non-Hodgkin's lymphoma cells. The combination of Rituximab and an LPAAT-beta inhibitor resulted in a 2-fold increase in apoptosis compared with either agent alone. To assess the combination of Rituximab and a LPAAT-beta inhibitor in vivo, groups of athymic mice bearing s.c. human Ramos lymphoma xenografts were treated with the LPAAT-beta inhibitor CT-32228 i.p. (75 mg/kg) daily for 5 d/wk x 4 weeks (total 20 doses), Rituximab i.p. (10 mg/kg) weekly x 4 weeks (4 doses total), or CT-32228 plus Rituximab combined. Treatment with either CT-32228 or Rituximab alone showed an approximate 50% xenograft growth delay; however, complete responses were only observed when the two agents were delivered together. CONCLUSIONS: These data suggest that Rituximab, combined with a LPAAT-beta inhibitor, may provide enhanced therapeutic effects through apoptotic mechanisms.

In vitro drug release studies from the polymeric hydrogels based on HEA and HPMA using 4-[(E)-[(3Z)-3-(4-(acryloyloxy)benzylidene)-2-hexylidene]methyl]phenyl acrylate as a crosslinker.

Novel crosslinker, 4-[(E)-[(3Z)-3-(4-(acryloyloxy)benzylidene)-2-hexylidene]methyl]phenyl acrylate (AMA) was synthesized using (2Z, 6E)-2,6-bis(4-hydroxybenzylidene)cyclohexanone (HBC) and acryloyl chloride. Two types of crosslinked polymeric hydrogels were prepared from 2-hydroxyethyl acrylate (HEA) and 2-hydroxypropyl methacrylate (HPMA) monomers using AMA as a crosslinking agent. 2',4-dichloro-5'-fluoro-1-ene-2-(4-hydroxyphenyl)phenone (EHP) (J. Bio Active Compat. Polym. 18 (2003) 219) was used as a drug molecule for monitoring the releasing behaviour of the hydrogels. Morphology of the hydrogels was characterized using optical microscopy (OM) and Scanning Electron Microscopy (SEM) techniques. Several modifications were made in the experimental sections to study the effect of crosslinking percentage (CLP), drug loading percentage (DLP), monomer type (HEA and HPMA) and the pH. Totally 18 experiments were carried out to study the desired parameters in the hydrogels. The drug-releasing rate was monitored by the absorption appeared at 330.5 nm using UV spectrometer. It was found that the releasing rate of the drug from the polymeric hydrogels was dependent on the crosslinking density, drug loading percentage, monomer type and pH of the medium.