Tumors of the Bladder, Kidney, and Intestine of F344 Rats and Liver of B6C3F1 Mice Administered o-Nitroanisole in Feed

Tumors of the Bladder, Kidney, and Intestine of F344 Rats andLiver of B6C3F₁ Mice Administered o-Nitroanisole in Feed. IRWIN,R. D., CHHABRA, R., EUSTIS, S., PINTER, A., AND PREJEAN, J.D. 1996). Fundam. Appl. Toxicol. 30, 1–12. o-Nitroanisole, a mutagenic intermediate used in the manufactureof azo dyes, was administered in feed for 2 years at concentrationsof 0, 222, 666, or 2000 ppm to groups of 60 male and 60 femaleF344 rats. No significant increase in neoplasms occurred inthese groups of rats. Additional (stop exposure) groups of 60male and 60 female F344 rats received diets containing 0, 6000,or 18,000 ppm for 27 weeks followed by maintenance on controldiets for up to an additional 77 weeks. Survival of the stopexposure groups was reduced because of the development of chemicalrelated neoplasms of the urinary bladder. After 13, 28, 40,and 65 weeks on study, 10 rats per group were necropsied andevaluated for the presence of chemical associated lesions. Hyperplasiaof the epithelium of the urinary bladder was significantly increasedat all interim evaluations. A transitional cell carcinoma wasobserved at the 13-week evaluation in one male rat that received18,000 ppm and thereafter transitional cell neoplasms of thebladder were present in male and female rats at each interimevaluation. Adeno matous polyps of the large intestine weresignificantly increased in groups that received 6000 or 18,000ppm. In addition carcino mas of the large intestine were presentin four males and two females that received 18,000 ppm. Hyperplasiaof the transitional epithelium of the renal pelvis was significantlyincreased in groups of rats that received 6000 or 18,000 ppmand transitional cell papillomas were observed in three malesand one female that received 18,000 ppm. Transitional cell carcinomasof the kidney occurred in one male that received 6000 ppm andsix males and one female that received 18,000. Groups of 60male and 60 female B6C3F₁, mice received dietary concentrationsof 0, 666, 2000, or 6000 ppm o-nitroanisole for 2 years. Nostop exposure study was conducted with mice. The only neoplasticresponse observed in mice was in the liver of males; hepatocellularadenomas or carcino mas were increased in groups of male micethat received 2000 or 6000 ppm. No increase in neoplasms associatedwith chemical exposure occurred in female mice.     

Pulmonary Immunotoxicity of Inhaled Ammonium Metavanadate in Fisher 344 Rats

Male Fisher 344 rats were exposed to 2 mg vanadium(V)/m³ (asammonium metavanadate NH⁴VO³, 0.32 µm MMD) atmospheresfor 8 hr/day for 4 days in a nose-only exposure system. In exposedrats, lung V burdens increased in a time-dependent fashion.Analysis of lung cells and lavage fluid 24 hr after the finalexposure suggested that tissue damage and a strong inflammatoryresponse was elicited; numbers of neutrophil and small macrophages(M), as well as levels of lavageable protein and lactate dehydrogenase,were significantly elevated as compared with levels observedwith air-exposed rats. Vanadium also affected pulmonary alveolarM (PAM) capacities to produce and respond to immunoregulatingcytokines. Inducible PAM production of tumor necrosis factor-awas significantly inhibited, as was the ability to increasecell surface Class II/I-A molecule expression in response tointerferon- (rFN-). PAM from V-exposed hosts were also inhibitedin their ability to be primed by EFN- to produce superorideanion and hydrogen peroxide in response to stimulation withopsonized zy-mosan. These studies indicate that short-term repeatedexposure of rats to atmospheric V, at levels encountered inan occupational setting, can alter host pulmonary immunomocompetence,with one major effect occurring at the level of cytokine-relatedfunctions. These alterations may be underlying mechanisms forthe well-documented increases in bronchopulmonary infectionsand cancers in workers chronically exposed to V-containing atmospheres.     

Retinoid-Induced Hypertriglyceridemia in Rats Is Mediated by Retinoic Acid Receptors

Retinoids in clinical use today are known to induce hypertriglyceridemiaas one of their major side effects. The purpose of the presentstudy was to determine, in an appropriate animal model, if retinoid-inducedhypertriglyceridemia is mediated by retinoic acid receptors(RARs) and/or by retinoid X receptors (RXRs). Oral gavage ofmale Fischer rats with 13-cis-retinoic acid for 6 days causeda rapid and sustained increase in serum triglycerides that wasreversible within 4 days posttreatment In subsequent experiments,rats were treated by gavage once daily for 3 days with variousretinoids, and serum triglyceride levels were determined 24hr after the last treatment without fasting. All-trans-and 13-cis-retinoicacid, which can be converted to both RAR and RXR agonists, and9-cis-retinoic acid, an RAR/RXR pan-agonist, caused dose-dependentincreases in serum triglycerides at doses that did not causeweight loss or mucocutaneous toxicity. Ro 13–6298 andAGN 190121, two RAR-specific agonists, caused dose-dependentincreases in serum triglycerides, although Ro 13–6298only induced hypertriglyceridemia at weight-suppressive doses.Two RXR-selective agonists, LG100268 and AGN 191701, failedto induce hypertriglyceridemia or weight loss up to the highestdoses tested. A structural isomer of AGN 190121 that does notactivate RARs or RXRs, AGN 190727, did not induce hypertriglyceridemia.Hypertriglyceridemia induced by AGN 190121 was significantlyinhibited by co-treatment with an RAR-selective antagonist,AGN 193109. Taken together, these data provide strong evidencethat retinoid-induced hypertriglyceridemia is mediated, at leastin part, by RARs. These data also suggest that RXR-specificagonists may have reduced potential to induce hypertriglyceridemiarelative to RAR-active retinoids.     

The Developmental Toxicity of Ethylene Glycol Diethyl Ether in Mice and Rabbits

Timed-pregnant CD-1 outbred Albino Swiss mice and New ZealandWhite rabbits were dosed by gavage with ethylene glycol diethylether (EGdiEE) in distilled water during major organogenesis.Mice were dosed on Gestational Days (gd) 6 through 15 (0, 50,150, 500, or 1000 mg/kg/day) and rabbits on gd 6 through 19(0, 25, 50, or 100 mg/kg/day). Maternal clinical status wasmonitored daily during treatment. At termination (gd 17, mice;gd 30, rabbits), confirmed-pregnant females (22–24 pergroup, mice; 26–32 per group, rabbits) were evaluatedfor clinical status and gestational outcome; each live fetuswas examined for external, visceral, and skeletal malformations.In mice, no maternal mortality was observed, but maternal bodyweight gain during gestation and treatment, and at terminationwas reduced at 1000 mg/kg/day. The reduction of maternal bodyweight gain during gestation was secondary to embryo/fetal toxicity,i.e., reduced gravid uterine weight as a consequence of decreasedlitter size and fetal weight. The no-observed adverse effectlevel (NOAEL) for developmental toxicity was 50 mg/kg/day. At150 mg/kg/day the number of litters of mice with malformed fetuseswas increased. At 500 mg/kg/day fetal body weight was reduced,and malformation incidence was significantly increased. Exencephalyand fused ribs were observed most often. In rabbits, maternalbody weight was unaffected by treatment even though 6% maternalmortality was observed at 100 mg/kg/day. The developmental NOAELwas 25 mg/kg/day. Malformations were increased at 50 mg/kg/day,short tail, small spleen, fused sternebrae, and fused rib cartilagewere observed most often. In summary, oral administration ofEGdiEE to mice and rabbits during organogenesis produced profoundadverse developmental effects even in the absence of significantmaternal toxicity. Developmental effects in rabbits were morevaried.     

Reproductive Study of Acrolein on Two Generations of Rats

Four groups of 30 male and 30 female rats were intubated with70 daily doses of acrolein at levels of 0, 1, 3, or 6 mg/kgin a dosing volume of 5 ml/kg. Rats within each dosing group(F₀ generation) were then assigned to a 21-day period of cohabitationand dosing for females continued through cohabitation gestationand lactation. Males were euthanized after cohabitation. F₁generation rats were chosen from pups, and a similar pretreatment,cohabitation, gestation, and lactation regimen was accomplishedresulting in F₂ generation pups. Reproductive parameters, bodyweights, food consumption, and clinical signs were recordedand necropsies were carried out on all treated animals. Histopathologicexams were accomplished on selected reproductive tissues. Inaddition, gross lesions, target tissues, stomachs, and lungswere examined. For the most part, reproductive parameters wereunaffected by acrolein treatment with the exception of reducedpup weights in the F₁ generation pups at the high-dose level(6 mg/kg/day). Gastric lesions were noted consistently in high-doseanimals and some mid-dose (3 mg/kg/day) rats. Erosions of glandularmucosa and hyperplasia/hyper keratosis of the forestomach werethe most frequent stomach lesions observed. Effects on bodyweight gains were noted frequently for the high-dose animalsand achieved statistical sig nificance in the mid-dose animalson several occasions. Mortality in all high-dose animals waselevated relative to control animals. Acrolein, therefore, cannotbe considered a selective reproductive toxin in the rat, butdoes produce toxicological effects down to a dosing level of3 mg/kg/day.     

Interspecies Differences in the Phagocytic Activity of Pulmonary Macrophages Subjected to Acidic Challenge

Examining interspecies differences in response to ambient pollutantsis an essential component of risk assessment. The potentialhazard to public health from the inhalation of acid sulfateaerosols is of current concern. A significant biological targetis the pulmonary macrophage, which provides a primary defenseof the respiratory region of the lungs. One essential functionof these cells is phagocytosis of particles. This study assessedthe effects of acidic environments on the phagocytic activityof pulmonary macrophages obtained by lavage from humans andthree species of laboratory animals commonly used in acid aerosoltoxicology studies, namely, rats, rabbits, and guinea pigs.Cells were incubated with polystyrene latex particles in mediaacidified by addition of sulfuric acid. The percentage of cellswhich were phagocytic, as well as the relative number of particlesingested by these cells, was found to decrease with increasingacidity for all species. The ranking of response in order ofdecreasing sensitivity to acidic challenge was as follows: guineapig>rat>rabbit>human.     

Disclosure,Apology, and Offer Programs: Stakeholders’ Views of Barriers to and Strategies for Broad Implementation

Context: The Disclosure, Apology, and Offer (DA&O) model, a response to patient injuries caused by medical care, is an innovative approach receiving national attention for its early success as an alternative to the existing inherently adversarial, inefficient, and inequitable medical liability system. Examples of DA&O programs, however, are few. Methods: Through key informant interviews, we investigated the potential for more widespread implementation of this model by provider organizations and liability insurers, defining barriers to implementation and strategies for overcoming them. Our study focused on Massachusetts, but we also explored themes that are broadly generalizable to other states. Findings: We found strong support for the DA&O model among key stakeholders, who cited its benefits for both the liability system and patient safety. The respondents did not perceive any insurmountable barriers to broad implementation, and they identified strategies that could be pursued relatively quickly. Such solutions would permit a range of organizations to implement the model without legislative hurdles. Conclusions: Although more data are needed about the outcomes of DA&O programs, the model holds considerable promise for transforming the current approach to medical liability and patient safety.     

Postoperative Heart Block in Children with Common Forms of Congenital Heart Disease: Results from the KID Database

Postoperative Heart Block in Congenital Heart Disease. Introduction: Cardiac conduction system injury is a cause of postoperative cardiac morbidity following repair of congenital heart disease (CHD). The national occurrence of postoperative complete heart block (CHB) following surgical repair of CHD is unknown. We sought to describe the occurrence of and costs related to postoperative CHB following surgical repair of common forms of CHD using a large national database. Methods and Results: Retrospective, observational analysis performed over a 10‐year period (2000–2009) using the Kids’ Inpatient Database (KID). Visits for patients ≤24 months of age were identified who underwent surgical repair of ventricular septal defects (VSD), atrioventricular canal defects (AVC), and tetralogy of Fallot (TOF). Patients were identified who were diagnosed with postoperative CHB, further identifying those requiring a new pacemaker placement during the same hospitalization. Costs associated with visits were calculated. There were 16,105 surgical visits: 7,146 VSD, 3,480 AVC, and 5,480 TOF. There was a decrease in postoperative mortality (P = 0.0001) with no significant change in postoperative CHB. Hospital stay and cost were higher with CHB and placement of a permanent pacemaker. Repair of AVC (OR 1.77; [1.32–2.38]) was associated with a higher rate of postoperative CHB. Length of hospital stay and total cost were significantly increased with the development of postoperative CHB and increased further with placement of a permanent pacemaker. Conclusion: There has been little change over time in the frequency of postoperative CHB in patients undergoing repair of VSD, AVC, and TOF. Postoperative CHB results in major added cost to the healthcare system. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1349‐1354, December 2012)