Developmental Toxicity of Dichloroacetonitrile: A By-Product of Drinking Water Disinfection

Developmental Toxicity of Dichloroacetonitrile: A By-productof Drinking Water Disinfection. SMITH, M. K., RANDALL, J. L.,STOBER, J. A., AND READ, E. J. (1989). Fundam. Appl. Toxicoi.12, 765–772. Dichloroacetonitrile (DCAN), a by-productof drinking water disinfection formed by reactlon of chlorinewith background organic materials, was evaluated for its developmentaleffects in pregnant Long-Evans rats. Animals were dosed by oralintubation on Gestation Days 6=18 (plug = 0) with 0, 5, 15,25, or 45 mg/kg/day. Tricaprylin was used as a vehicle. Thehighest dose tested (45 mg/kg) was lethal in 9% of the damsand caused resorption of the entire litter in 60% of the survivors.Embryolethality averaged 6% per litter at the low dose and 80%at the high dose and was statistically significant at 25 and45 mg/kg/day. The incidence of soft tissue malformations wasdose related and was statistically significant at doses toxicto the dam (45 mg/kg). These anomalies were principally in thecardiovascular (interventricular septal defect, levocardia,and abnormalities of the major vessels) and urogenital (hydronephrosis,rudimentary bladder and kidney, fused ureters, pelvic hernia,cryptorchidism) systems The frequency of skeletal malformations(fused and cemcal ribs) was also, dose related and significantlyincreased at 45 mg/kg. The no-observed-adverse-effect dose fortoxicity in pregnant Long-Evans rats was established by statisticalanalysis to be 15 mg/kg/day.     

Alveolar Retention and Clearance of Insoluble Particles in Rats Simulated by a New Physiology-Oriented Compartmental Kinetics Model

Alveolar Retention and Clearance of Insoluble Particles in RatsSimulated by a New Physiology-Oriented Compartmental KineticsModel. STOBER, W., MORROW, P. E., AND MORAWIETZ, G. (1990).Fundam Appl. Toxtcol. 15,329–349. A physiology-orientedcompartmental kinetics model of alveolar retention of inhaledinsoluble paniculate matter in rat lungs was proposed in a recentpaper, (W. Stober, P. E. Morrow, and M. D. Hoover, 1989, Fundam.Appl. Toxicol. 13, 823–843), and the retention patternsobtained with the model for a hypothetical set of input dataappeared to simulate phenomena which were observed in inhalationstudies with Fischer 344 rats. The present paper representsthe results of applying the new model for simulations of theactual experimental retention data of five different inhalationstudies with Fischer 344 rats exposed to three different materials.The experimental data showed that model adjustments had to bemade in order to account for clearance effects that appearedto be influenced by the age of the animals. After these adjustmentswere made and an appropriate set of values for the model parametersdescribing the respective exposure conditions was used, themodel was constrained to represent the empirical data of allof the studies by one unique set of parameter values. Changesin particular values of this set were considered to be acceptableonly if they reflected changes of relevant properties of theinhaled paniculate matter. The final simulations did not completelycomply with this self-imposed criterion. However, the degreeof compliance and the simulation quality achieved with a minimumof parameter variations seem to be unprecedented in retentionmodeling. The results of the study encourage attempts for furtherrefining the present model     

Clinical performance of extended zirconia frameworks for fixed dental prostheses: two-year results

Summary  The purpose of this prospective cohort study was to assess the performance of tooth-supported, extended zirconia, fixed dental prostheses (FDPs). Thirty FDPs with span-lengths between 36 and 46 mm (mean: 40·33 mm), four to seven units and with connector dimensions of ∼9 mm² were inserted (19 in the posterior region, 11 including anterior teeth) using glass–ionomer cement and assessed (aesthetic evaluation, failures, hypersensitivity/tooth vitality, secondary caries, pocket depth, decementation and chipping) at baseline and after 2 years. Differences between baseline and 2-year recall were analysed using the Wilcoxon signed-rank test for matched pairs. There were five failures. One FDP revealed a core fracture at the base of the connector, probably caused by a damage induced during fabrication. Two FDPs had to be recemented, one abutment tooth had to be treated endodontically and one cohesive failure of the veneer was observed. There were no significant changes of pocket depth and hypersensitivity between baseline and 2-year recall. The aesthetics were rated as excellent by the patients at both baseline and recall. Two year clinical results of extended zirconia based FDPs with 9 mm² connectors are promising.     

Hepatocarcinogenicity of Chioral Hydrate, 2-Chloroacetaldehyde, and Dichioroacetic Acid in the Male B6C3F1 Mouse

The chlorinated acetaldehydes, chloral hydrate (CH) and 2-chloroacetaldehyde(CAA), have been identified as chlorination by-products in finisheddrinking water supplies. Although both chemicals are genotoxic,their potential for carcinogenicity had not been adequatelyexplored. The studies reported here are chronic bioassays conductedwith male B6C3F1 mice exposed to levels of 1 g/liter CH and0.1 g/liter CAA via the drinking water for 104 weeks. Distilledwater (H₂O) served as the untreated control and dichloroaceticacid (DCA; 0.5 g/liter), another chlorine disinfection by-product,was included. The mean daily ingested doses were approximately166 mg/kg/day for CH, 17 mg/kg/day for CAA, and 93 mg/kg/dayfor DCA. Evaluations included mortality, body weight, organweights, gross pathology, and histopathology. The primary targetorgan was the liver as the organ weights and pathological changesin the other organs (spleen, kidneys, and testes) were comparablebetween the treated groups and the H₂O control group. Liverweights were increased for all three test chemicals at the terminaleuthanasia with the greatest increase seen in the CH and DCAgroups. Hepatocellular necrosis was induced by all three testchemicals, and it was also most prevalent and severe in theCH and DCA groups. A significant increase in the prevalenceof liver tumors was seen for all three chemicals. The strongestresponse was with DCA, in which 63% of the 104-week survivorshad hepatocellular carcinomas (carcinomas) and 42% possessedhepatocellular adenomas (adenomas) and the combined prevalencefor carcinomas plus adenoma was 75%. The corresponding prevalencerate for carcinomas, adenomas, and combined tumors were 46,29, and 71% 31, 8, and 38% and 10, 5, and 15% for CH, CAA, andH₂O, respectively. In addition to the tumors we evaluated theprevalence of a possible preneoplastic lesion, the hepatocellularhyperplastic nodule (nodules), a lesion which occurred in allthree treated groups but not in the H₂O group.     

The Carcinogenicity of Dichloroacetic Acid in the Male B6C3F1 Mouse

Groups of male B6C3F, mice (N = 50) were provided drinking watercontaining 2 g/liter sodium chloride (control) and 0.05,0.5,and 5 g/liter dichloroacetic acid (DCA). Treatment of 30 animalsin each group was carried out to 60 or 75 weeks. In a separateexperiment, mice exposed to 3.5 g/liter DCA and the correspondingacetic acid control group were killed at 60 weeks. Groups of5 mice were killed at 4, 15, 30, and 45 weeks. Time-weightedmean daily doses of 7.6, 77, 410, and 486 mg/kg/day were calculatedfor 0.05, 0.5, 3.5, and 5 g/liter DCA treatments. Animals exposedto 3.5 and 5 g/liter DCA had final body weights that were 87and 83%, respectively, of the control value. Relative liverweights of 136, 230, and 351% of the control value were measuredfor 0.5, 3.5, and 5 g/liter, respectively. At 60 weeks micereceiving 5.0 g/liter DCA had a 90% prevalence of liver neoplasiawith a mean multiplicity of 4.50 tumors/animal. Exposure to3.5 g/ liter DCA for 60 weeks resulted in a 100% tumor prevalencewith an average of 4.0 tumors/ animal. The prevalence of liverneoplasia and tumor multiplicity at 60 and 75 weeks in the 0.05g/liter DCA (24.1%; 0.31 tumors/animal) and in the 0.5 g/litergroup (11.1%; 0.11 tumors/animal) did not differ significantlyfrom the control value (7.1% and 0.07 tumors/animal). No livertumors were found in the group treated with acetic acid. Hyperplasticnodules were seen in the 3.5 (58%; 0.92/animal) and 5 g/literDCA groups (83% 1.27/animal). There was a significant positivedose-related trend in the age-adjusted prevalence of liver tumors.These data confirm the hepatocar-cinogenicity of DCA administeredin the drinking water to male B6C3F, mice for 60 weeks. Theresults together with those in an earlier report from this laboratorysuggest, for the conditions under which these assays were conducted,a threshold concentration of at least 0.5 g/liter followed bya steep rise to a maximum tumor incidence at 2 g/liter DCA.     

Subchronic Inhalation of Diethylamine Vapor in Fischer-344 Rats: Organ System Toxicity

Subchronic Inhalation of Diethylamine Vapor in Fischer-344-Rats:Organ System Toxicity. LYNCH, D. W., MOORMAN, W. J., STOBER,P., LEWIS, T. R., AND IVERSON, W. O. (1986). Fwidam. Appl. Toxicol.6, 559–565. Male and female Fischer 344 (F-344) rats wereexposed at 0, 25, or 250 ppm diethylamine (DEA) vapor, 6.5 hrper day, 5 days per week, for 24 weeks in order to assess cardiacand other organ system toxicity. Scheduled sacrifices were performedfollowing 30, 60, and 120 days of exposure. During the first2 weeks of exposure, the rats exposed at 250 ppm DEA did notgain weight. After 2 weeks, however, the rate of weight gainof these rats was greater than that of controls. Nevertheless,mean body weights for both sexes of rats exposed at 250 ppmDEA remained depressed compared to controls throughout the study.Sneezing, tearing, and reddened noses were seen in rats exposedat 250 ppm DEA. Histopathologic examinations revealed lesionsof the nasal mucosa of rats exposed at 250 ppm DEA (rats exposedat 25 ppm were not evaluated). These lesions of the respiratoryepithelium consisted of squamous metaplasia, suppurative rhinitis,and lymphoid hyperplasia. There were no pronounced treatment-relatedeffects on organ weights, hematology, or clinical chemistryindices except for blood urea nitrogen which was elevated inrats of both sexes exposed at 250 ppm DEA for 24 weeks. In contrastto the highdose animals, no treatment-related effects were observedin rats intermittently exposed at 250 ppm DEA for up to 24 weeks.No evidence of cardiotoxicity was seen in rats exposed to eitherDEA concentration for up to 24 weeks.     

Chloroform Inhibition of 1,2-Dimethylhydrazine-Induced Gastrointestinal Tract Tumors in the Fisher 344 Rat

The effect of chloroform (CHCl₃), administered at 0, 900, and1800 mg/liter in the drinking water, on the carcinogenic potencyof 1,2-dimethylhydrazine (DMH) was investigated. Groups of 40male Fisher 344 rats were given one of the three drinking watersolutions for 39 weeks following the subcutaneous injectionof 200 mg/kg DMH, a known gastrointestinal (GI) tract carcinogenin this animal strain. When tumors from the GI tract were pooledthere was a highly significant (p < 0.001) decrease in totalnumber of tumors per group with increasing concentration ofdrinking water CHG3. In the control group (0 mg/liter CHCl₃),14/39 (36%) of the animals developed tumors of the GI tract,including the duodenum, jejunum, stomach, cecum, and colon.In contrast, the incidence of tumors in the two groups of ratsgiven CHCl₃ in the drinking water was significantly lower (p< 0.001; 900 mg/liter CHCl₃, 12.8%; 1800 mg/liter CHCl₃,12.5%). A similar relationship was obtained when colon tumorswere analyzed independently (p = 0.01). The incidence of totalcolon tumors obtained in the control group of this study (10/39,26%) agrees well with the previous study by B. S. Reddy, K.Watanabe, and J. H. Weisburger (1977, Cancer Res. 37, 4156–4159)conducted in the same rat strain (7/30, 23%). These resultsdemonstrate that CHCl₃ in the drinking water inhibits carcinogenesisin the rat GI tract.