Evaluation of An Inpatient Pharmacy Consult on Discharge Medications in Bariatric Surgery Patients.

PURPOSE: To evaluate the impact of an inpatient pharmacy consult on discharge medications following bariatric surgery. METHODS: A pharmacy consult for discharge medication review for bariatric surgery patients was instituted at an academic medical center. The intervention included conducting a medication history, reviewing home medications for updates post-bariatric surgery, creating and documenting a discharge medication plan, and providing patient education. The impact of the intervention was evaluated by comparing medication classes, doses, and formulations prescribed during the intervention relative to a historical control group. RESULTS: The study included 85 patients who received pharmacist intervention and 167 patients who did not receive pharmacist intervention following bariatric surgery. The prescription of an extended-release medication at discharge in the intervention group was reduced by 19.3% (28.7% vs. 9.4%, p = 0.0005). For patients on hypertension medications, 94.0% had their regimen reduced in the intervention group compared with 37.5% of patients in the control group (p < 0.001). Of patients on insulin at baseline, 87.5% of patients in the intervention group had dose reductions at discharge vs. 66.7% of patients in the control group (p = 0.37). No patients in the intervention group were discharged with oral antihyperglycemic medications or non-insulin injectable medications vs. 33.3% (p = 0.12) and 20.0% (p = 0.47), respectively, in the control group. Readmission rates at 30 days were insignificantly lower in the intervention group (3.5% vs. 4.2%, p = 1). CONCLUSIONS: Clinical pharmacist involvement in the discharge medication reconciliation process for bariatric surgery patients reduced prescribing of unadjusted medication classes, doses, and drug formulations.

Canine discrimination of ovarian cancer through volatile organic compounds.

Ovarian cancer has a high mortality rate due to its unclear symptomology and the lack of precise early detection tools. If detected in the first stage, over 90% of patients reach remission. As such, developing a reliable method of early detection is crucial in reducing the mortality rate of the disease. One potential method would be to identify specific biomarkers that are unique to ovarian cancer, which could be detected using a blood test. While this can be done using gas chromatography - mass spectrometry (GC-MS), identifying these biomarkers is an enormous task. One way to expedite the process is to utilize trained scent detection canines. In this study, dogs who were previously trained to respond to positive blood samples from ovarian cancer patients were then tested on their ability to recognize samples prepared by micro-preparative gas chromatography (MP-GC) techniques. MP-GC employed a gradient-cooled glass tube connected to the GC outlet to collect GC eluents containing the plasma-derived volatiles in positive blood samples. These post-column fractions were collected at the exit of the GC according to their eluent times (i.e., 0-15 min, 15-25 min and 25-35 min or 0-35 min) and these full or fractional collections were presented to the trained dogs to judge their responses. Dogs' time spent investigating the odor was used as an indication of odor recognition and was significantly longer on the early (0-15 min) and middle (15-25 min) fractions of the ovarian cancer than the late (25-35 min) fraction of plasma odorants or either the negative fractions or distractors odorants. These findings suggest that characteristic odor biomarkers of ovarian cancer for dogs may exist in the relatively small and more volatile compounds. Additionally, variation between dogs suggests that there may be a number of different biomarkers that can be used to identify ovarian cancer.

Pharmacy-led initiative for improving peri-operative medication reconciliation among bariatric surgical patients: what is the role?

BACKGROUND: Multiple medication changes are common after bariatric surgery, but pharmacist assistance in this setting is not well described. This study evaluated the feasibility and effectiveness of a pharmacy-led initiative for facilitating discharge medicine reconciliation after bariatric surgery. METHODS: A standardized post-operative pharmacy consult evaluation was conducted on bariatric surgery inpatients at a single academic center starting 1/2/2019. Retrospective chart review evaluated patient characteristics, medication changes, and 30-day outcomes pre-intervention (7/2018-12/2018) and post-intervention (1/2019-12/2019). Two-sample t tests or binomial tests were used for continuous or categorical variables, respectively; a p-value of < 0.05 was deemed statistically significant. RESULTS: A total of 353 patients were identified for study inclusion (n = 158 pre-intervention, n = 195 post-intervention) with a mean age of 45 years, 87% female, and 71% sleeve gastrectomy. Overall pharmacy consultation compliance was 94% with 77.0% of home medication recommendations followed. Non-narcotic pain medication prescription use significantly increased (39% pre- vs. 54% post-intervention; p < 0.001). At discharge, the average number of changed or new medications significantly increased (3.7 ± 1.2 pre- vs. 4.2 ± 1.8 post-intervention; p = 0.003) while the average number of stopped medications was similar (1.2 ± 1.5 pre- vs. 1.5 ± 1.9 post-intervention; p = 0.09). Anti-hypertensive medications were decreased or stopped substantially more often with pharmacist input (44.7% pre- vs. 85.4% post-intervention; p < 0.001). Three medication-related readmissions happened pre-intervention with none post-intervention. Outpatient medication-related phone calls did considerably increase (31% pre- vs. 39% post-intervention; p = 0.04), while overall 30-day readmissions significantly decreased (7.6% pre- vs. 1.5% post-intervention; p = 0.04). CONCLUSIONS: Inpatient pharmacy consultation facilitated rapid alteration to more appropriate therapy for hypertension management and significantly increased use of non-narcotic pain medications upon discharge among bariatric surgery patients. Improved protocol adherence is anticipated with program maturity and patient education interventions will be deployed to address outpatient phone calls.

Reducing Early Readmissions after Ventral Hernia Repair with the Americas Hernia Society Quality Collaborative.

BACKGROUND: Early readmission after ventral hernia repair (VHR) can hinder patient recovery and increase resource use. The objective of this study was to evaluate the effectiveness of the Americas Hernia Society Quality Collaborative Early Readmission Reduction Initiative in reducing early readmissions after VHR. STUDY DESIGN: Risk factors for early readmission and best practices of surgeons with the lowest readmission rates after VHR were determined through collaborative learning. Two interventions for reducing early readmissions were developed: a structured questionnaire administered to patients within 1 week after discharge from the hospital or an early clinic visit after discharge and before a regularly scheduled postoperative visit. Multivariable logistic regression was used to evaluate the impact of these interventions on early readmission. RESULTS: Use of the questionnaire and early clinic visit was tracked in 3,007 patients. Of these, 343 received the questionnaire (2.6% readmission rate), 761 had an early clinic visit after discharge (3.0% readmission rate), 138 had both (4.3% readmission rate), and 1,765 patients received neither (5.9% readmission rate). After controlling for factors associated with early readmissions, administration of the questionnaire (odds ratio 0.42; 95% CI 0.21 to 0.84; p < 0.05) or having an early clinic visit (odds ratio 0.48; 95% CI 0.30 to 0.76; p < 0.05) were both associated with reduced odds for readmission. CONCLUSIONS: The Americas Hernia Society Quality Collaborative Early Readmission Reduction Initiative successfully reduced readmissions after VHR using a structured questionnaire or early clinic visit implemented after discharge and before routine 30-day postoperative follow-up.

Neoplastic and nonneoplastic liver lesions induced by dimethylnitrosamine in Japanese medaka fish.

Small fish models have been used for decades in carcinogenicity testing. Demonstration of common morphological changes associated with specific mechanisms is a clear avenue by which data can be compared across divergent phyletic levels. Dimethylnitrosamine, used in rats to model human alcoholic cirrhosis and hepatic neoplasia, is also a potent hepatotoxin and carcinogen in fish. We recently reported some striking differences in the mutagenicity of DMN in lambda cII transgenic medaka fish vs. Big Blue(®) rats, but the pre-neoplastic and neoplastic commonalities between the two models are largely unknown. Here, we focus on these commonalities, with special emphasis on the TGF-ß pathway and its corresponding role in DMN-induced hepatic neoplasia. Similar to mammals, hepatocellular necrosis, regeneration, and dysplasia; hepatic stellate cell and "spindle cell" proliferation; hepatocellular and biliary carcinomas; and TGF-ß1 expression by dysplastic hepatocytes all occurred in DMN-exposed medaka. Positive TGF-ß1 staining increased with increasing DMN exposure in bile preductular epithelial cells, intermediate cells, immature hepatocytes and fewer mature hepatocytes. Muscle specific actin identified hepatic stellate cells in DMN-exposed fish. Additional mechanistic comparisons between animal models at different phyletic levels will continue to facilitate the interspecies extrapolations that are so critical to toxicological risk assessments.

Development of normal human colon cell cultures to identify priority unregulated disinfection by-products with a carcinogenic potential.

Research was initiated to develop an in vitro system to identify disinfection by-products with a potential to transform normal human colonocytes into malignant cells. Tribromomethane and bromochloroacetic acid, rodent colon carcinogens, dibromonitromethane and tribromonitromethane, recently identified in drinking water, and azoxymethane, a classic colon carcinogen, were tested for the ability to transform NCM460 cells. The chronic toxicity was determined for the series of trihalomethanes, haloacetic acids and halonitromethanes as well as NCM460 cell enzymatic capabilities. The order of cytotoxicity was halonitromethanes > haloacetic acids > trihalomethanes. Cytotoxicity within a series increased with the degree of bromination and decreased with the molecular weight. The genotoxicity profile was similar to that for cytotoxicity. Enzymatic analysis demonstrated that NCM460 cells possess glutathione-S transerase-1-1 and CYP450 activity similar to that measured in the large intestine. NCM460 cells were exposed to 10(-6) M of the test chemicals for three days. While NCM460 cells from all treatments had the ability to grow in soft agar to some extent, only cells exposed to azoxymethane or tribromomethane were able to grow in media lacking serum and growth factors. When sub cultured, NCM460 cells exposed to 10(-9) M azoxymethane for three weeks formed colonies with morphology distinct from untreated cells.

Detection of early gene expression changes by differential display in the livers of mice exposed to dichloroacetic acid.

Dichloroacetic acid (DCA) is a major by-product of water disinfection by chlorination. Several studies have demonstrated the hepatocarcinogenicity of DCA in mice when administered in drinking water. The mechanism of DCA carcinogenicity is not clear and we speculate that changes in gene expression may be important. In order to analyze early changes in gene expression induced by DCA treatment we used the differential display method. Mice were treated with 2 g/l DCA in drinking water for 4 weeks. Total RNAs were obtained from livers of both control and treated mice for analysis. Of approximately 48 000 bands on the differential display gels representing an estimated 96% of RNA species, 381 showed differences in intensity. After cloning and confirmation by both reverse-northern and northern analyses, six differentially expressed genes were found. The expression of five of these genes was suppressed in the DCA-treated mice while one was induced. After sequencing, four genes were identified and two were matched to expressed sequence tags through the BLAST program. These genes are alpha-1 protease inhibitor, cytochrome b5, stearoyl-CoA desaturase and carboxylesterase. Stearoyl-CoA desaturase was induced approximately 3-fold in the livers of DCA-treated mice and the other three genes were suppressed approximately 3-fold. Stearoyl-CoA desaturase, cytochrome b5 and carboxylesterase are endoplasmic reticulum membrane-bound enzymes involved in fatty acid metabolism. The expression pattern of four of these genes was similar in DCA-induced hepatocellular carcinomas and the 4 week DCA-treated mouse livers. The expression of stearoyl-CoA desaturase and one of the unidentified genes returned to control levels in the carcinomas. Understanding the roles and interactions between these genes may shed light on the mechanism of DCA carcinogenesis.

Subchronic sodium chlorate exposure in drinking water results in a concentration-dependent increase in rat thyroid follicular cell hyperplasia.

Chlorine dioxide (ClO2) is an effective drinking water disinfectant, but sodium chlorate (NaClO3) has been identified as a potentially harmful disinfection by-product. Studies were performed to describe the development of thyroid lesions in animals exposed to NaClO3 in the drinking water. Male and female F344 rats and B6C3F1 mice were exposed to 0, 0.125, 0.25, 0.5, 1.0, or 2.0 g/L NaClO3 for 21 days. Additional male F344 rats were exposed to 0, 0.001. 0.01. 0.1, 1.0. or 2.0 g/L NaClO3 for 90 days. Female F344 rats were exposed to 0, 0.5, 1.0, 2.0, 4.0, or 6.0 g/L of NaClO3 for 105 days. Thyroid tissues were processed by routine methods for light microscopic examination, and follicular cell hyperplasia was diagnosed using a novel method. Thyroid hormone levels were altered significantly after 4 and 21 days. NaClO, treatment induced a concentration-dependent increase in the incidence and severity of thyroid follicular cell hyperplasia. Male rats are more sensitive to the effects of NaClO3 treatment than females. Follicular cell hyperplasia was not present in male or female B6C3F1 mice. These data can be used to estimate the human health risk that would be associated with using ClO2, rather than chlorine, to disinfect drinking water.

Group F streptococcal bacteremia complicating a Bartholin's abscess.

BACKGROUND: Group F streptococci are gram-positive cocci typically isolated from wound infections and abscesses. Bacteremia with group F streptococcus is uncommon, and the lower gynecologic tract has not been reported as a source. We report a case of a Bartholin's abscess leading to group F streptococcal bacteremia. CASE: A 31-year-old female noted fever and rigors 30 min after manipulation of a 3-day-old vulvar abscess. An empty Bartholin's gland abscess was found on examination, and blood cultures grew beta-hemolytic group F streptococci. The patient was treated with ampicillin/sulbactam, symptoms improved, and follow-up blood cultures revealed no growth. CONCLUSION: Group F streptococci are known to inhabit various body sites and have a predilection for forming abscesses; however, bacteremia is infrequent. They have occasionally been identified in true infections of the genitourinary tract but only very rarely in Bartholin's abscesses. This case of group F streptococcal bacteremia following self-drainage of a Bartholin's abscess constitutes the first such description in the medical literature.

Carcinogenicity of chloral hydrate administered in drinking water to the male F344/N rat and male B6C3F1 mouse.

Male B6C3F1 mice and male F344/N rats were exposed to chloral hydrate (chloral) in the drinking water for 2 years. Rats: Measured chloral hydrate drinking water concentrations for the study were 0.12 g/L, 0.58 g/L, and 2.51 g/L chloral hydrate that yielded time-weighted mean daily doses (MDDs) of 7.4, 37.4, and 162.6 mg/kg per day. Water consumptions, survival, body weights, and organ weights were not altered in any of the chloral hydrate treatments. Life-time exposures to chloral hydrate failed to increase the prevalence (percentage of animals with a tumor) or the multiplicity (tumors/animal) of hepatocellular neoplasia. Chloral hydrate did not increase the prevalence of neoplasia at any other organ site. Mice: Measured chloral hydrate drinking water concentrations for the study were 0.12 g/L, 0.58 g/L, and 1.28 g/L that gave MDDs of 13.5, 65.0, and 146.6 mg/kg per day. Water consumptions, survival, body and organ weights, were not altered from the control values by any of the chloral hydrate treatments. Enhanced neoplasia was observed only in the liver. Prevalence and multiplicity of hepatocellular carcinoma (HC) were increased only for the high-dose group (84.4%; 0.72 HC/animal; p < or = 0.05). Values of 54.3%; 0.72 HC/animal and 59%; 1.03 HC/animal were observed for the 13.5- and 65.0-mg/kg per day treatment groups. Prevalence and multiplicity for the control group were 54.8%; 0.74 HC/animal. Hepatoadenoma (HA) prevalence and multiplicity were significantly increased (p < or = 0.05) at all chloral hydrate concentrations: 43.5%; 0.65 HA/animal, 51.3%; 0.95 HA/animal and 50%; 0.72 HA/animal at 13.5, 65.0, and 146.6 mg/kg per day chloral hydrate compared to 21.4%; 0.21 HA/animal in the untreated group. Altered foci of cells were evident in all doses tested in the mouse, but no significant differences were observed over the control values. Hepatocellular necrosis was minimal and did not exceed that seen in untreated rats and mice. Chloral hydrate exposure did not alter serum chemistry and hepatocyte proliferation in rats and mice or increase hepatic palmitoyl CoA oxidase in mice at any of the time periods monitored. It was concluded that chloral hydrate was carcinogenic (hepatocellular neoplasia) in the male mouse, but not in the rat, following a lifetime exposure in the drinking water. Based upon the increased HA and combined tumors at all chloral hydrate doses tested, a no observed adverse effect level was not determined.

The disinfection by-products dichloro-, dibromo-, and bromochloroacetic acid impact intestinal microflora and metabolism in Fischer 344 rats upon exposure in drinking water.

Human consumption of chlorinated drinking water has been linked epidemiologically to bladder, kidney, and rectal cancers. The disinfection by-product (DBP) dichloroacetic acid is a hepatocarcinogen in Fischer 344 rats and B6C3F1 mice. The objective of this study is to determine the effect of the DBPs dichloro-, bromochloro-, and dibromoacetic acids (DCA, BCA, DBA) on intestinal microbial populations and their metabolism, with emphasis on enzymes involved in the bioactivation of procarcinogens and promutagens. One-month-old male Fischer 344 rats were provided water ad libitum containing 1 g/l DCA, BCA, or DBA for up to 5 weeks. At 1, 3, and 5 weeks of treatment, beta-glucuronidase (GLR), beta-galactosidase (GAL), beta-glucosidase (GLU), nitroreductase (NR), azoreductase (AR), and dechlorinase (DC) activities were determined in cecal and small and large intestinal homogenates. After 5 weeks of treatment, intestinal populations were enumerated on selective media. Cecal GAL (DCA, BCA, DBA) and GLR (DCA, DBA) activities were reduced after 1 and 3 weeks of treatment and GAL activity was elevated at 5 weeks (BCA). Large intestinal GAL (DCA, BCA) and GLU (DCA, BCA, DBA) activities were elevated after 5 weeks of treatment. Week 5 cecal AR (DCA, BCA, DBA), NR (DCA), and DC (DCA, DBA) activities were reduced. Even though some significant changes in intestinal populations were observed, use of selective media was not sensitive enough to explain fluctuations in enzyme activity. Haloacetic acids in the drinking water alter intestinal metabolism, which could influence bioactivation of promutagens and procarcinogens in the drinking water.

Origin and distribution of potassium bromate-induced testicular and peritoneal mesotheliomas in rats.

Tissue sections were examined from a 2-year bioassay of male Fischer 344 rats treated with potassium bromate administered in drinking water. All animals exhibiting peritoneal mesotheliomas also had mesotheliomas of the tunica vaginalis testis mesorchium (the reverse was not true), and the correlation of these 2 types of mesotheliomas was highly significant (r2 = 0.98). Mapping of the tunica vaginalis tumors at all time points and at all bromate concentrations revealed a pattern of increasing incidence of tumor formation on the mesothelium of the tunica vaginalis testis as a function of proximity to the mesorchial ligament. Thus, the mesorchium appears to be the major mesothelial target site for potassium bromate-mediated carcinogenesis. The frequency of occurrence of mesotheliomas by location was tunica vaginalis testis (25%), mesosplenium (20%), mesentery (10%), mesojejunum/mesocolon (8%), bladder (6.5%), mesogastrium (13%), liver serosa (5%), and kidney, small intestine, and rectum (1% each). A complete cross-section of the rat testis was prepared and used to construct a complete map of the mesothelium. Any attempt to determine the role of local dose and tissue susceptibility for the purpose of interspecies risk extrapolation must take into account the complex anatomy and physiology of this region of the visceral and testicular suspensory apparatus. Improved histologic approaches are needed for adequate assessment of this delicate suspensory system.

Morphologic analysis correlates with gene expression changes in cultured F344 rat mesothelial cells.

The gene expression pattern of mesothelial cells in vitro was determined after 4 or 12 h exposure to the rat mesothelial, kidney, and thyroid carcinogen and oxidative stressor potassium bromate (KBrO(3)). Gene expression changes observed using cDNA arrays indicated oxidative stress, mitotic arrest, and apoptosis in treated immortalized rat peritoneal mesothelial cells. Increases occurred in oxidative stress responsive genes HO-1, QR, HSP70, GADD45, GADD153, p21(WAF1/CIP16), GST's, GAPDH, TPX, and GPX-1(0); transcriptional regulators c-jun, c-fos, jun B, c-myc, and IkappaB; protein repair components Rdelta, RC10-II, C3, RC-7, HR6B ubiquitin-conjugating enzyme and ubiquitin; DNA repair components PCNA, msh2, and O-6 methylguanine DNA methyltransferase; lipid peroxide excision enzyme PLA2; and apoptogenic components TNFalpha, iNOS1 and FasL. Decreases occurred in bcl-2 (antiapoptotic), bax alpha, bad, and bok (proapoptotic) and cell cycle control elements (cyclins). Cyclin G and p14ink4b (which inhibit entry into cell cycle) were increased. Numerous signal transduction, cell membrane transport, membrane-associated receptor, and fatty acid biosynthesis and repair components were altered. Morphologic endpoints examined were number of mitotic figures, number of apoptotic cells, and antibody-specific localization of HO-1 (which demonstrated increased HO-1 protein expression). PCR analysis confirmed HO-1, p21(waf1/cip1), HSP70, GPX1, GADD45, QR, mdr1, PGHS, and cyclin D1 changes. A model for KBrO(3)-induced carcinogenicity in the F344 rat mesothelium is proposed, whereby KBrO(3) generates a redox signal that activates p53 and results in transcriptional activation of oxidative stress and repair genes, dysregulation of growth control, and imperfect DNA repair leading to carcinogenesis.

Hepatocarcinogenicity in the male B6C3F1 mouse following a lifetime exposure to dichloroacetic acid in the drinking water: dose-response determination and modes of action.

Male B6C3F, mice were exposed to dichloroacetic acid (DCA) in the drinking water in order to establish a dose response for the induction of hepatocellular cancer and to examine several modes of action for the carcinogenic process. Groups of animals were exposed to control, 0.05, 0.5, 1, 2, or 3.5 g/L DCA in the drinking water for 90-100 wk. Mean daily doses (MDD) of 8, 84, 168, 315, and 429 mg/kg/d of DCA were calculated. The prevalence (percent of animals) with hepatocellular carcinoma (HC) was significantly increased in the 1-g/L (71%), 2-g/L (95%), and 3.5-g/L (100%) treatment groups when compared to the control (26%). HC multiplicity (tumors/animal) was significantly increased by all DCA treatments-0.05 g/L (0.58), 0.5 g/L (0.68), 1 g/L (1.29), 2 g/L (2.47), and 3.5 g/L (2.90)-compared to the control group (0.28). Based upon HC multiplicity, a no-observed-effect level (NOEL) for hepatocarcinogenicity could not be determined. Hepatic peroxisome proliferation was significantly increased only for 3.5 g/L DCA treatment at 26 wk. and did not correlate with the liver tumor response. The severity of hepatotoxicity increased with DCA concentration. Below 1 g/L, hepatotoxicity was mild and transient as demonstrated by the severity indices and serum lactate dehydrogenase activity. An analysis of generalized hepatocyte proliferation reflected the mild hepatotoxicity and demonstrated no significant treatment effects on the labeling index of hepatocytes outside proliferative lesions. Consequently, the induction of liver cancer by DCA does not appear to be conditional upon peroxisome induction or chemically sustained cell proliferation. Hepatotoxicity, especially at the higher doses, may exert an important influence on the carcinogenic process.

Time- and dose-dependent development of potassium bromate-induced tumors in male Fischer 344 rats.

Potassium bromate (KBrO3) is a rodent carcinogen and a nephro- and neurotoxicant in humans. KBrO3 is used in cosmetics and food products and is a by-product of water disinfection by ozonization. KBrO3 is carcinogenic in the rat kidney, thyroid, and mesothelium and is a renal carcinogen in the male mouse. The present study was designed to investigate the relationship of time and dose to bromate-induced tumors in male Fischer 344 (F344) rats and to provide some insight into the development of these tumors. KBrO3 was dissolved in drinking water at nominal concentrations of 0, 0.02, 0.1, 0.2, and 0.4 g/L and administered to male F344 rats as the sole water source for 12, 26, 52, 78, or 100 wk. Renal cell tumors were present after 52 wk of treatment only in the high-dose group. Mesotheliomas developed after 52 wk of treatment on the tunica vaginalis. Mesotheliomas were present at sites other than the testicle after 78 wk of treatment, indicating that their origin was the testicular tunic. Thyroid follicular tumors were present as early as 26 wk in 1 rat each from the 0.1- and 0.2-g/L groups. The present study can be used as a basis for the determination of dose-time relationships of tumor development for a better understanding of KBrO3-induced cancer.

Carcinogenicity of potassium bromate administered in the drinking water to male B6C3F1 mice and F344/N rats.

Ozone has been proposed for water disinfection because it is more efficient than chlorine for killing microbes and results in much lower levels of carcinogenic trihalomethanes than does chlorination. Ozone leads to formation of hypobromous acid in surface waters with high bromine content and forms brominated organic by-products and bromate. The carcinogenicity and chronic toxicity of potassium bromate (KBrO3) was studied in male B6C3F1 mice and F344/N rats to confirm and extend the results of previous work. Mice were treated with 0, 0.08, 0.4, or 0.8 g/L KBrO3 in the drinking water for up to 100 wk, and rats were provided with 0, 0.02, 0.1, 0.2, or 0.4 g/L KBrO3. Animals were euthanatized, necropsied, and subjected to a complete macroscopic examination. Selected tissues and gross lesions were processed by routine methods for light microscopic examination. The present study showed that KBrO3 is carcinogenic in the rat kidney, thyroid, and mesothelium and is a renal carcinogen in the male mouse, KBrO3 was carcinogenic in rodents at water concentrations as low as 0.02 g/L (20 ppm; 1.5 mg/kg/day). These data can be used to estimate the human health risk that would be associated with changing from chlorination to ozonation for disinfection of drinking water.

Hepatotoxicity of the drinking water disinfection by-product, dichloroacetic acid, in the medaka small fish model.

Recent studies have shown that dichloroacetic acid (DCA), a by-product of chlorination of public water supplies, is carcinogenic to both rats and mice. However, conflicting data have left the mechanism of DCA carcinogenicity, vital to assessment of human health risk, unclear. Elucidation of this mechanism in another animal model at a different phyletic level than rodents would advance the risk assessment process for government agencies concerned with regulation and provision of safe drinking water. The Japanese medaka (Oryzias latipes), a well characterized small fish model, is being used increasingly for carcinogenicity testing because of its low cost, ease of maintenance and carcinogen sensitivity. In this study, 6-week-old medaka were exposed to diethylnitrosamine (DEN, a known initiator), followed by continuous exposure to 0.5 or 2.0 g/l DCA in the ambient water, over a 4 week period. At both exposure concentrations, changes in the liver included marked hepatocellular cytoplasmic vacuolation, cytomegaly, karyomegaly, nuclear atypia and multifocal areas of hepatocellular necrosis and loss as early as week two of DCA exposure. The majority of the hepatocellular cytoplasmic vacuoles were shown by periodic acid Schiff (PAS) staining to contain large amounts of glycogen. These elevated glycogen levels may reflect a disruption in the enzyme pathways for glycolysis. The total cellular changes seen in this short-term exposure regimen are compatible with preneoplastic changes seen in rats and mice exposed to DCA. The results of this study strengthen the role of the Japanese medaka as a suitable species in carcinogenicity testing as well as its implementation in the risk assessment process for DCA across several phyletic levels.

Assessment of the mutagenicity of dichloroacetic acid in lacI transgenic B6C3F1 mouse liver.

Dichloroacetic acid (DCA) is a chlorination byproduct found in finished drinking water. When administered in drinking water this chemical has been shown to produce hepatocellular adenomas and carcinomas in B6C3F1 mice over the animal's lifetime. In this study, we investigated whether mutant frequencies were increased in mouse liver using treatment protocols that yielded significant tumor induction. DCA was administered continuously at either 1.0 or 3.5 g/l in drinking water to male transgenic B6C3F1 mice harboring the bacterial lacI gene. Groups of five or six animals were killed at 4, 10 or 60 weeks and livers removed. At both 4 and 10 weeks of treatment, there was no significant difference in mutant frequency between the treated and control animals at either dose level. At 60 weeks, mice treated with 1.0 g/l DCA showed a 1.3-fold increase in mutant frequency over concurrent controls (P = 0.05). Mice treated with 3.5 g/l DCA for 60 weeks had a 2.3-fold increase in mutant frequency over the concurrent controls (P = 0.002). The mutation spectrum recovered from mice treated with 3.5 g/l DCA for 60 weeks contained G:C-->A:T transitions (32.79%) and G:C-->T:A transversions (21.31%). In contrast, G:C-->A:T transitions comprised 53.19% of the recovered mutants among control animals. Although only 19.15% of mutations among the controls were at T:A sites, 32.79% of the mutations from DCA-treated animals were at T:A sites. This is consistent with the previous observation that the proportion of mutations at T:A sites in codon 61 of the H-ras gene was increased in DCA-induced liver tumors in B6C3F1 mice. The present study demonstrates DCA-associated mutagenicity in the mouse liver under conditions in which DCA produces hepatic tumors.