Toxicity associated with ingestion of a polyacrylic acid hydrogel dog pad.

Superabsorbent sodium polyacrylate polymeric hydrogels that retain large amounts of liquids are used in disposable diapers, sanitary napkins, and other applications. These polymers are generally considered "nontoxic" with acute oral median lethal doses (LD50) >5 g/kg. Despite this favorable toxicity profile, we identified a novel toxic syndrome in dogs and rats following the ingestion of a commercial dog pad composed primarily of a polyacrylic acid hydrogel. Inappropriate mentation, cerebellar ataxia, vomiting, and intention tremors were observed within 24 h after the ingestion of up to 15.7 g/kg of the hydrogel by an adult, castrated male Australian Shepherd mix. These observations prompted an experimental study in rats to further characterize the toxicity of the hydrogel. Adult, female Sprague Dawley rats ( n = 9) were assessed before and after hydrogel ingestion (2.6-19.2 g/kg over 4 h) using a functional observation battery and spontaneous motor activity. Clinical signs consistent with neurotoxicity emerged in rats as early as 2 h after the end of hydrogel exposure, including decreased activity in an open field, hunched posture, gait changes, reduced reaction to handling, decreased muscle tone, and abnormal surface righting. Hydrogel-exposed rats also had reduced motor activity when compared with pre-exposure baseline data. Rats that ingested the hydrogel did not develop nervous system lesions. These findings support the conclusion that some pet pad hydrogel products can induce acute neurotoxicity in animals under high-dose exposure conditions.

Polyacrylic acid attenuates ethylene glycol induced hyperoxaluric damage and prevents crystal aggregation in vitro and in vivo.

The study explores calcium oxalate crystal inhibiting characteristic of polyacrylic acid (pAA), an anionic polymer in in vitro and in vivo. Animals were divided into 5 groups where group 1 served as control, group 2 were made hyperoxaluric by supplementing with Ethylene glycol (EG) 0.75% (v/v) for 30 days. Group 3, 4 & 5 were also given with EG and treated simultaneously with 2.5, 5 & 10 mg of pAA/kg of body weight, respectively. Urine, serum and tissue analyses along with histological studies were performed at the end of the 30 days study. In vitro crystallization was significantly inhibited by pAA and further it was supported by particle size analyses, XRD and FT-IR studies. Toxicological analyses showed that pAA was safe to use in animals at concentrations below 100 mg/kg BW. In vivo anti-urolithic study showed significant improvement in urinary lithogenic factors (calcium, oxalate, phosphate, citrate & magnesium) and renal function parameters (creatinine, urea and protein). Tissue analyses on anti-oxidant enzyme activity and lipid peroxides showed maintenance of tissue antioxidant status in the pAA supplemented rats and histological studies demonstrated the nephroprotection offered by pAA and were concurrent to the biochemical analyses. Supplementation of pAA not only reduces the crystal aggregation but also regulates the expression and localization of crystal inhibiting proteins and gene expression of inflammatory cytokines in experimental animals. In summary, pAA is a potent anti-urolithic agent in rats and we can propose that 10 mg/kg body weight is the effective dosage of pAA and this concentration can be used for further studies.

Utility and safety of commercially available injection laryngoplasty materials in a rabbit model.

OBJECTIVE: To demonstrate foreign body and chronic inflammatory reaction of commercially available injection materials using the rabbit vocal fold paralysis model. STUDY DESIGN: Animal study. METHODS: The left recurrent laryngeal nerve was identified and divided at the tracheoesophageal groove. Amounts (100 µL) of phosphate-buffered saline (PBS), polyacrylamide hydrogel (Aquamid; Ferrosan A/S, Søborg, Denmark), calcium hydroxyapatite (Radiesse; BioForm Medical Inc., San Mateo, CA), or hyaluronic acid derivative (Rofilan; Rofil Medical International, Breda, Netherlands) were injected into the left vocalis muscle. Six months later, the larynx was harvested. Hematoxylin/eosin and Masson trichrome staining were performed to compare inflammatory and foreign body reactions, granuloma development, and relative vocal fold areas among groups. RESULTS: Compared with the PBS (control) group, the Aquamid, Radiesse, and Rofilan groups exhibited only mild chronic inflammatory reactions that did not significantly differ among groups, or from controls (P > 0.05). However, the Aquamid and Radiesse groups exhibited moderate foreign body reactions that were significantly greater than those of controls (P < 0.05). No foreign body granuloma formed in any group. All test groups exhibited significant increases in vocal fold areas at 6 months (P < 0.05). CONCLUSIONS: Although commercially available injection materials induced more foreign body reactions than a control injection of PBS, no foreign body granuloma developed and the augmented vocal fold area was maintained until 6 months after injection.

The targeted behavior of thermally responsive nanohydrogel evaluated by NIR system in mouse model.

Thermally responsive poly(N-isopropylacrylamide-co-acrylamide) (P(NIPA-co-AAm)) nanohydrogels were synthesized in this study by free-radical precipitation polymerization method. Different lower critical solution temperatures (LCST) of nanohydrogels were obtained by modulating the amount of AAm and characterized by measuring their transmittances of the particle solutions at 500 nm. The diameters within the range of 50-450 nm were achieved by manipulating the amount of sodiumdodecyl sulfate (SDS). Near infrared dye NIRD-12, with excitation and emission wavelengths at 772 nm and 814 nm, was entrapped into the P(NIPA-co-AAm) nanohydrogels for in vivo animal study. The thermally targeted behavior of the nanohydrogels was evaluated by the in vivo fluorescence imaging on different groups of denuded mice, with or without S180 tumors and with or without hyperthermia treatment. Results indicated that this kind of thermally responsive nanohydrogel could only accumulate in the tissue with higher temperature, no matter normal tissue and tumor site. The thermally targeted behavior is passive and non-specific. The targeted location can be selected by hyperthermia treatment and manipulating the suitable LCST of nanohydrogel. Results indicated that the thermally responsive P(NIPA-co-AAm) nanohydrogel could be used as an attracting thermally targeted carrier for drugs, especially for anti-cancer drugs.

Wastewater treatment polymers identified as the toxic component of a diamond mine effluent.

The Ekati Diamond Mine, located approximately 300 km northeast of Yellowknife in Canada's Northwest Territories, uses mechanical crushing and washing processes to extract diamonds from kimberlite ore. The processing plant's effluent contains kimberlite ore particles (< or =0.5 mm), wastewater, and two wastewater treatment polymers, a cationic polydiallydimethylammonium chloride (DADMAC) polymer and an anionic sodium acrylate polyacrylamide (PAM) polymer. A series of acute (48-h) and chronic (7-d) toxicity tests determined the processed kimberlite effluent (PKE) was chronically, but not acutely, toxic to Ceriodaphnia dubia. Reproduction of C. dubia was inhibited significantly at concentrations as low as 12.5% PKE. Toxicity identification evaluations (TIE) were initiated to identify the toxic component of PKE. Ethylenediaminetetraacetic acid (EDTA), sodium thiosulfate, aeration, and solid phase extraction with C-18 manipulations failed to reduce PKE toxicity. Toxicity was reduced significantly by pH adjustments to pH 3 or 11 followed by filtration. Toxicity testing with C. dubia determined that the cationic DADMAC polymer had a 48-h median lethal concentration (LC50) of 0.32 mg/L and 7-d median effective concentration (EC50) of 0.014 mg/L. The anionic PAM polymer had a 48-h LC50 of 218 mg/L. A weight-of-evidence approach, using the data obtained from the TIE, the polymer toxicity experiments, the estimated concentration of the cationic polymer in the kimberlite effluent, and the behavior of kimberlite minerals in pH-adjusted solutions provided sufficient evidence to identify the cationic DADMAC polymer as the toxic component of the diamond mine PKE.

Evaluation of the mucosal irritation potency of co-spray dried Amioca/poly(acrylic acid) and Amioca/Carbopol 974P mixtures.

The purpose of this study was to evaluate the biocompatibility of different Amioca/poly(acrylic acid) and Amioca/Carbopol 974P co-spray dried mixtures with an alternative mucosal irritation test using slugs. The irritation potential of the mixtures was measured by the amount of mucus produced during a repeated 30-min contact period. Additionally, membrane damage was assessed by measuring the protein and enzyme release from the body wall of slugs after treatment. All the Amioca/poly(acrylic acid) co-spray dried mixtures (50:50 and 25:75 ratios) induced slight irritation of the mucosal tissue as was demonstrated by the significantly increased mucus production however no increased protein and enzyme release was detected. Co-spray dried Amioca/Carbopol 974P mixtures containing 40% and more Carbopol 974P demonstrated a significantly higher mucus production and release of cytosolic LDH, indicating membrane damage. The total mucus production of the slugs treated with the co-spray dried mixtures containing up to 20% Carbopol 974P was significantly higher compared to the blank slugs. However, these mixtures induced no membrane damage since no additional effect on the protein release and no enzyme release was detected. By co-spray drying up to 20% Carbopol 974P could be incorporated without showing a distinct sign of irritation. These mixtures can be considered as potentially safe bioadhesive carriers.

Comparative and experimental pathology of fibrosing colonopathy.

Although the occurrence of fibrosing colonopathy is temporally associated with the introduction of high-strength pancreatic enzyme supplements, its pathogenesis remains uncertain. The UK case-control study showed fibrosing colonopathy to be associated with high doses of high-strength pancreatic enzyme supplements and with a group of brands which occupy only 30% of the market. Two alternative hypotheses were proposed to explain the aetiology of fibrosing colonopathy: exposure to high levels of enzymes or to as yet unidentified components of the formulation. Comparison of the anatomical pathology of fibrosing colonopathy with that of previously encountered forms of obstructive gastrointestinal pathology, such as stricturing lesions due to potassium chloride preparations and nonsteroidal anti-inflammatory drugs, confirmed it to be a previously unencountered, long-segment lesion of the colon. Thus the use of the descriptive term 'stricture' is a misnomer leading to much clinical confusion when discussing obstructive bowel pathology in cystic fibrosis patients. Gavage studies in the rat with one of the two monomers (ethyl acrylate) forming the methacrylic acid copolymer (Eudragit L30D55) used for the enteric coating of the high-strength pancreatic enzyme supplements, have shown pathology comparable to fibrosing colonopathy. These findings prompted a series of exploratory studies in adolescent pigs. After seven days caecal gavage of Eudragit L30D55 at doses of 10, 50 or 500 mg/kg/day (comparable to human intake), extensive fibrosing colonopathy-like changes, inclusive of dense submucosal fibrosis, were noted at all dose levels in seven out of nine animals. Similar studies of the monomer components of the Eudragit L30D55 copolymer, at dose levels of 0.015 to 50 mg/kg/day, representing possible residues in Eudragit L30D55, did not produce comparable changes. The conclusion is that, although the precise mechanisms have not been elucidated, the role of enteric coatings containing Eudragit L30D55 in the pathogenesis of fibrosing colonopathy requires urgent further study.

Experimental polyacrylamide-induced acute injury in rat lung.

We recently reported the first case of accidental aspiration of polyacrylamide occurring in a 26-year-old man. The patient developed severe airway obstruction and parenchymal lung damage and died. Autopsy revealed numerous polyacrylamide particles in his lungs, as well as extensive bronchiolar and alveolar damage. Gas chromatographic and mass spectrometric assessment of the lung tissue failed to reveal polyacrylamide activity, although assessment of the suspending solvent of the polyacrylamide showed a pattern characteristic of an aliphatic hydrocarbon mixture with a prominent dodecane peak. This experimental study was performed to determine the nature and extent of damage to rat bronchial and alveolar epithelia following endotracheal instillation of polyacrylamide, hydrocarbon mixture (petroleum distillate), dodecane (C12H26), or normal saline. The rat lungs were examined grossly and microscopically 10 min and 24, 72, and 96 h after endotracheal instillation, following inflation and fixation with 10 percent buffered formaldehyde. Gross examination revealed congested, mottled visceral pleural surfaces in the rats treated with polyacrylamide and dodecane. There were no pleural exudates or effusions. Microscopically, vascular engorgement, bronchiolitis, and focal pneumonia were observed. Vascular engorgement was most pronounced at 72 to 96 h in rat lungs treated with polyacrylamide and dodecane and was moderate at 24 h in rats treated with petroleum distillate. Focal organizing pneumonia was marked at 96 h in rats treated with petroleum distillate, at 72 h in those treated with polyacrylamide, and at 24 h in those treated with dodecane. The saline-treated control animals showed no change. Our findings suggest that polyacrylamide, dodecane, and petroleum distillate are strong irritants to the airways. However, a direct obstructive/mechanical effect of the polyacrylamide upon the airway has not been excluded. Airway exposure to polyacrylamide may result in lung injury secondary to the polyacrylamide itself, its suspending agents, or both.

Studies of the developmental toxicity of polycarboxylate dispersing agents.

Three linear polycarboxylate compounds, two linear polyacrylates (90,000 MW and 4,500 MW) and one linear polyacrylate-maleate copolymer (12,000 MW), were tested for their teratogenic potential in female Sprague Dawley rats. These polymers, which were tested as sodium salts, are used as dispersing agents in detergent formulations at levels of 1-5%. All compounds were administered by gavage during organogenesis (days 6-15 of pregnancy). No adverse effects on development were seen with any of the three compounds at any of the doses tested. The highest dose, and therefore the minimum no-effect dose, for the three linear polymers was 1125 mg/kg/day for the 90,000 MW polyacrylate, 3000 mg/kg/day for the 4,500 MW polyacrylate, and 6670 mg/kg/day for the polyacrylate-maleate copolymer. Based on these data, these compounds are not developmentally toxic, even at very high dose levels.

Development of a toxicity evaluation program for dental materials and products. II. Screening for systemic toxicity.

A series of systemic toxicity tests for various types of compounds are presented with illustrative data and discussed in regard to their relevance as potential screening tests for dental compounds and products. In developing and marketing a new dental material, it is important not only to ensure safety for the patient but also for the dentist, dental assistant, and laboratory worker who routinely handles and uses the product. Data are presented on a number of commercially available dental products as well as various chemical entities, which were tested by one or more of the methods described.