Developmental Toxicity Evaluation of Ethylene Glycol by Gavage in New Zealand White Rabbits

Artificially inseminated New Zealand white (NZW) rabbits wereadministered ethylene glycol (EG) by gavage on Gestational Days(GD) 6 through 19 at doses of 0, 100, 500, 1000, or 2000 mg/kg/day,with 23–24 inseminated animals per group. Clinical signswere recorded and water consumption was measured daily; doeswere weighed on GD 0, 6–19, 25, and 30. At necropsy (GD30), maternal liver, kidney, and gravid uterine weights wererecorded. Histopathologic examination was performed on kidneysfrom 10 does/dose and for all unscheduled deaths. Ovarian corporalutea were counted and uterine implantation sites (total sites,resorptions, dead and live fetuses) were recorded. All livefetuses were weighed, sexed, and examined for external, visceral,and skeletal malformations and variations. EG resulted in profoundmaternal toxicity at 2000 mg/kg/day (42% mortality; three earlydeliveries and one spontaneous abortion) associated with renalpathology and unaccompanied by any other indicators of maternaltoxicity. Renal lesions at 2000 mg/kg/day involved the corticalrenal tubules and included intraluminal oxalate crystals, epithelialnecrosis, and tubular dilatation and degeneration. No dose-relatedmaternal toxicity occurred at 100–1000 mg/kg/day. Therewas no indication of developmental toxicity at any dose tested,including no effects on pre- or postimplantation loss, numberof fetuses, fetal body weight, or sex ratio (% male fetuses)per litter, and no evidence of teratogenicity. The "no observableadverse effect level" (NOAEL) for maternal toxicity was therefore1000 mg/kg/day and the NOAEL for developmental toxicity wasat least 2000 mg/kg/day in this study. The sensitivity of NZWrabbits relative to that of Sprague—Dawley rats and Swissmice for maternal and developmental toxicity from gavage administrationof EG during organogenesis can be determined for maternal toxicity:rabbits>mice>rats, and for developmental toxicity, mice>>rats >> rabbits.     

Subchronic Toxicity of Cupric Sulfate Administered in Drinking Water and Feed to Rats and Mice

Subchronic Toxicity of Cupric Sulfate Administered in DrinkingWater and Feed to Rats and Mice. HÉBERT, C. D., ELWELL,M. R., TRAVLOS, G. S., FITZ, C. J., AND BUCHER, J. R. (1993).Fundam. Appl. Toxicol. 21, 461–475. The effects of acute poisoning by cupric sulfate in a numberof species are well known; however, the effects of chronic low-levelingestion of cupric sulfate are less well characterized. Becauseexposure of humans to cupric sulfate may occur through drinkingwater, food, soil, or ambient air, subchronic toxicity studieswere conducted in male and female F344/N rats and B6C3F₁ miceby the drinking water (2-week exposure) and dosed feed (2-and13-week exposure) routes. Animals were evaluated for histopathology,clinical pathology, reproductive toxicity, and tissue metalaccumulation, and target organs were examined by a variety ofspecial stains and by electron microscopy to characterize theobserved lesions. In drinking water, cupric sulfate concentrationsof 300 to 100 ppm produced no ill effects, whereas concentrationsof 3000 to 30,000 ppm were lethal to rats and mice within 2weeks. In feed, cupric sulfate concentrations of 4000 to 16,000ppm caused significant reductions in body weight gain in bothspecies in the 2- and 13-week studies. Hyperplasia and hyperkeratosisof the limiting ridge of the forestomach were present in bothspecies in the 2- and 13-week studies. Rats in the dosed feedstudies had a dose-related increase in inflammation in the liverand changes in clinical chemistry parameters which were indicativeof hepatocellular damage and cholestasis. Histologic changesin the kidneys of rats consisted of a dose-related increasein the number and size of eosinophilic protein droplets in theepithelial cytoplasm and the lumina of the proximal convolutedtubules. Droplets were larger and more numerous in males thanin females. Urinalysis results were suggestive of renal tubularepithelial damage. Iron staining of spleens from treated animalsindicated a marked depletion of iron stores in both male andfemale rats, but not in mice, while hematologic and clinicalchemistry alterations in rats in the 13-week study, along withhistologic changes in bone in the 2-week dosed feed study, wereindicative of a microcytic anemia. Cupric sulfate produced noadverse effects on any of the reproductive parameters measuredin rats or mice of either sex. These results indicate that cupricsulfate at high exposure levels is a hepatic and renal toxicant,as well as an inducer of anemia in rodents, with rats more sensitivethan mice following subchronic exposure.     

The Nominal Group Technique: A Research Tool for General Practice?

Qualitative methods are increasingly recognized as valuable,yet practitioners face difficult decisions in their choice ofmethod and the process of analysis. The nominal group techniquecombines quantitative and qualitative data collection in a groupsetting, and avoids problems of group dynamics associated withother group methods such as brainstorming, Delphi and focusgroups. Idea generation and problem solving are combined ina structured group process, which encourages and enhances theparticipation of group members. The stages involved in conductinga nominal group are described, and practical problems of itsuse in a health care setting are discussed with reference toa study of the priorities of care of diabetic patients, carersand health professionals. Some potential applications of thetechnique in audit and exploratory research are also outlined.     

Modification by Nickel of Instrumental Thermoregulatory Behavior in Rats1

Modification by Nickel of Instrumental Thermoregulatory Behaviorin Rats. WATANABE, C, WEISS, B., COX, C, AND ZIRIAX, J. (1990).Fundam. Appl. Toxicol. 14, 578–588. The effects of NiCl₂on the colonic temperature and thermoregulatory behavior (TRB)of rats were examined. TRB was evaluated in an instrumental(operant) setting in which rats were required to press a leverto obtain convectional heat (SEEK) or to avoid heat (ESCAPE).Orthogonal polynomial regression was used to describe the responsepatterns in both the SEEK and ESCAPE situations. Two milligramsper kilogram of Ni (ip) caused rapid, transient hypothermiaat an ambient temperature of 21°C. When given access toheat reinforcement, rats responded for heat at a lower rateimmediately after 2 or 5 mg/kg of Ni (up to 5–15 min)than after saline. Subsequently, response rates rose 30 minor more after Ni injection. A converse pattern was found withthe heat escape situation. These observations, confirmed bytwo contrasting procedures, indicate that the changes were thermoregulatoryin nature and cannot be explained by nonspecific sup-pressiveor excitatory effects of Ni. They further suggest that Ni-inducedhypothermia results from an altered body temperature set point.The subsequent reversal in behavior probably arises from a directaction of Ni on autonomic effector mechanisms. The origin andbiological significance of these findings require further investigation.Physical requirements and response topography are discussedas critical variables in the interpretation of experiments requiringsimilar responses under different ambient temperatures.     

FLUMAZENIL IN ALCOHOL WITHDRAWAL: A DOUBLE-BLIND PLACEBO-CONTROLLED STUDY

The purpose of the present study was to study -aminobutyricacid (GABA)-A receptor function in alcohol-dependent subjectsduring withdrawal, using the benzodiazepine antagonist flumazenil.In particular, we wanted to examine the hypotheses that an endogenousinverse agonist ligand at the GABA-A benzodiazepine receptor(GBzR) is active during withdrawal (in which case flumazenilshould be anxiolytic), or whether chronic alcohol intake resultsin a shift in sensitivity of the receptor in the inverse agonistdirection (in which case flumazenil should be anxiogenic). Resultsfrom 15 alcohol-dependent subjects in a double-blind placebo-controlledcross-over study showed that flumazenil was neither anxiolyticnor anxiogenic, although withdrawal scores were reduced duringthe course of the study. The fact that flumazenil was not anxiogenic,as it is in panic disorder, suggests that the GBzR is functioningdifferently in these two clinically similar conditions.     

Inhibition of 3,3',4,4',5-Pentachlorobiphenyl-Induced Chicken Embryotoxicity by 2,2',4,4',5,5'-Hexachlorobiphenyl

3,3',4,4',5-Pentachlorobiphenyl (pentaCB) caused a dose-dependentinduction of chicken embryolethality, malformations, edema,and liver lesions at doses ranging from 0.5 to 12.0 µg/kg.In contrast, no embryotoxicity was observed after treatmentwith 10, 25, or 50 mg/kg 2,2',4,4',5,5'-hexaCB. In eggs cotreatedwith 2.0 µ/kg, 3,3',4,4',5-pentaCB plus 10, 25, or 50mg/kg 2,2',4,4',5,5'-hexaCB, there was significant protectionfrom 3,3',4,4',5-pentaCB-induced embryo malformations, edema,and liver lesions, whereas no inhibition of embryolethalitywas observed. These results further extend the response-specificnonadditive interactions of binary mixtures of polychlorinatedbiphenyls (PCBs) and should be considered in the developmentof approaches for hazard assessment of PCB mixtures and relatedcompounds.     

Can One be a Good Doctor and have a Sexual Relationship with One's Patient?

This paper presents a qualitative exploration of social andsexual contact between general practitioners and their patients.Social contacts have been implicated in the development of sexualrelationships between members of the mental health professionsand their patients. However, there has been little examinationof the implications for general practitioners. Six focus groupswere conducted by teleconference with New Zealand general practitioners.Participant anonymity was maintained. Questions focused on issuesof social and sexual contact in general practice. Major themeswere extracted from the data. A range of definitions of ‘patient’,‘sexual contact’ and ‘social contact’were offered by the participants which demonstrated that ‘greyareas’ existed for them in relation to social and sexualrelationships with patients. Mandatory reporting of colleaguesfor alleged sexual misconduct was not supported, informal mechanismsbeing preferred. General practitioners need to be aware of potentialboundary violations in their practice. These issues are alsoimportant to address in the teaching of medical students, continuingmedical education, and in the development of appropriate guidelinesfor general practice.     

Subchronic Inhalation Toxicity Studies with Hydrochlorofluorocarbon 123 (HCFC 123)

Hydrochlorofluorocarbon 123 (HCFC 123) is one of the chemicalsbeing considered as a replacement for the chlorofluorocarbons.Four subchronic inhalation toxicity studies from 1 to 3 monthsin duration have been conducted with HCFC 123. One study utilizedrats and dogs, while the others were limited to rats only. Theexposure levels have ranged from 300 ppm up to 20,000 ppm. Althoughthe studies were conducted over a 14-year period, the resultswere consistent. In all studies, increases in liver weightswere seen at 1000 ppm and above; additionally, one showed thiseffect at 500 ppm. Histopathological findings were minimal,consisting primarily of focal necrosis in the liver of the dogsat 10,000 ppm. Induction of peroxisomal activity, lowering ofserum cholesterol and triglyceride levels, and an increase inurinary fluoride levels were also seen. The 4-hr LC₅₀ in therat has been reported as 35,000 ppm. At 20,000 ppm for 6 hr,the total daily dose on a concentration times time basis isalmost equal to the LC₅₀ yet, in the 4-week study, with 20 exposuresat this level, there was no mortality or even marked signs oftoxicity. There appeared to be no evidence for cumulative toxicityfrom multiple exposures in these studies. Overall, HCFC 123appears to have a low level of toxicity by the inhalation route.     

Reproductive Toxicity of Butylated Triphenyl Phosphate and Tricresyl Phosphate Fluids in F344 Rats

The effects of tricresyl phosphate (TCP) and butylated triphenylphosphate (BTP)-based hydraulic fluid on reproduction were studiedin F344 rats using a modification of the National ToxicologyProgram's Continuous Breeding Protocol. Groups of breeding pairsreceived single daily oral doses of an equal volume of either0, 0.6, 1.0 g BTP/kg or 0.4 g TCP/kg in sesame oil or 1.7 gneat BTP/kg for up to 135 days. A naive control group allowedto breed, but not dosed or handled daily, demonstrated thatdaily dosing and handling of the rats had no effect on reproduction.The fertility index and number of litters born were significantlydecreased in rats exposed to 1.0 and 1.7 g BTP/kg and 0.4 gTCP/kg. The number of pups per litter was significantly decreasedin the TCP group. A crossover mating experiment using 0.4 gTCP/kg/day and 1.0 g BTP/kg/day groups, each mated with vehiclecontrols, demonstrated that TCP caused 100% infertility in malerats but did not affect reproduction in females. BTP causeda significant decline in reproduction in female rats characterizedby low mating and fertility indices, decreased number of litters,and abnormal estrous cycles. Fertility was decreased in theBTP-dosed male rats. Both sexes of rats in the crossover experimentwith TCP and BTP had significant decreases in terminal bodyweights and increases in adrenal gland and liver weights. OnlyTCP-dosed male rats had significantly decreased testicular andepididymal weights. TCP-dosed female rats had increased ovarianweights, while BTP-dosed females had significantly lower uterineweights. The results of this study indicate that BTP and TCPare reproductive toxicants in F344 rats.