Comparative Toxicity of Arsine Gas in B6C3F1 Mice, Fischer 344 Rats, and Syrian Golden Hamsters: System Organ Studies and Comparison of Clinical Indices of Exposure

Comparative Toxicity of Arsine Gas in B6C3F₁ Mice, Fischer 344Rats, and Syrian Golden Hamsters: System Organ Studies and Comparisonof Clinical Indices of Exposure. BLAIR, P. C, THOMPSON, M. B.,MORRISSEY, R. E., MOORMAN, M. P., SLOANE, R. A., AND FOWLER,B. a. (1990). Fundam. Appl. Toxicol. 14, 776–787. In orderto examine possible species differences in response to arsineexposure, multiple inhalation studies consisting of acute (1-day),subacute (14- and 28-day), and subchronic (90-day) exposuresto this agent were conducted using three different species ofrodents. Evaluations of hematopoietic organs and alterationsin the heme biosynthetic pathway were the focus of these studies.Species used were B6C3F₁ mice (exposed 1, 14, or 90 days), Fischer344 rats (exposed 14, 28, or 90 days), and Syrian Golden hamsters(exposed 28 days). All arsine exposures were at concentrationsof 0.5, 2.5, or 5.0 ppm except for 90-day studies, in whichconcentrations were lowered to 0.025, 0.5, or 2.5 ppm. No changesin body weight gain were observed in either sex of mice or hamsters.The only decrease in body weight gain occurred in male ratsexposed to 5.0 ppm arsine for 28 days. Significant exposure-relatedincreases in relative spleen weights occurred in both sexesof mice and rats in the 0.5 (except 14-day female rats), 2.5,and 5.0 ppm exposure groups from all studies and in hamstersin the 2.5 and 5.0 ppm exposure groups. Generally, increasesin relative liver weight occurred in fewer exposure groups andwere of a lesser magnitude than increases in spleen weight.Other parameters affected included decreased packed cell volumes(mice, rats, and hamsters), hematol-ogy profiles (rats), andan increase in 6-aminolevulinic acid dehydratase activity inall species. Arsenic content was measured in livers of ratsafter 90 days of exposure. Concentrations increased in relationto atmospheric concentrations of arsine. Histopathological changesincluded increased hemosiderosis and extramedullary hematopoiesisin spleen and intracanalicular bile stasis (mice only) in liver.Additionally, bone marrow hyperplasia was observed in rats.Effects on other organs were not observed, suggesting that thehematopoietic system is the primary target for arsine. In conclusion,we have determined that the effects of arsine exposure uponmice, rats, and hamsters are similar. Most importantly, eventhough no effects on the hematopoietic system were observedfollowing a single exposure to 0.5 ppm arsine which is 10 timesthe Threshold Limit Value (TLV) set by the American Conferenceof Governmental Industrial Hygienists, repeated exposure to0.025 ppm (one-half the TLV) caused a significant anemia inrats.     

Developmental Toxicity Evaluation of Inhaled Nitrobenzene in CD Rats

Developmental Toxicity Evaluation of Inhaled Nitrobenzene inCD Rats. TYL, R. W., FRANCE, K. A., FISHER, L. C., DODD, D.E., PRITTS, I. M, LYON, J. P., O'NEAL, F. O., and KIMMERLE,G. (1987). Fundam. Appl. Toxicol. 8, 482–492. PregnantCD (Sprague–Dawley) rats were exposed to nitrobenzenevapor (CAS Registry No. 98-95-3) at 0, 1, 10, and 40 ppm (meananalytical values of 0.0, 1.06, 9.8, and 39.4 ppm, respectively)on gestational days (gd) 6 through 15 for 6 hr/day. At sacrificeon gd 21, fetuses were evaluated for external, visceral, andskeletal malformations and variations. Maternal toxicity wasobserved: weight gain was reduced during exposure (gd 6–9and 6–15) to 40 ppm, with full recovery by gd 21, andabsolute and relative spleen weights were increased at 10 and40 ppm. There was no effect of treatment on maternal liver,kidney, or gravid uterine weights, on pre- or postimplantationloss including resorptions or dead fetuses, on sex ratio oflive fetuses, or on fetal body weights (male, female, or total)per litter. There were also no treatment-related effects onthe incidence of fetal malformations or variations. In summary,during organogenesis in CD rats, there was no developmentaltoxicity (including teratogenicity) associated with exposureto nitrobenzene concentrations that produced some maternal toxicity(10 and 40 ppm) or that produced no observable maternal toxicity(1 ppm).     

Evaluation of the Developmental Toxicity of Ethylene Glycol Monohexyl Ether Vapor in Fischer 344 Rats and New Zealand White Rabbits

Evaluation of the Developmental Toxicity of Ethylene GlycolMonohexyl Ethyl Vapor in Fischer 344 Rats and New Zealand WhiteRabbits. TYL, R. W., BALLANTYNE, B., FRANCE, K. A., FISHER,L. C., KLONNE, D. R., AND PRITTS, I. M. (1989). Fundam Appl.Toxicol. 12, 269-280. Timed pregnant Fischer 344 rats and NewZealand White rabbits were exposed to vapor from ethylene glycolmonohexyl ether (EGHE, CAS No. 112-25-4) for 6 hr/day on gestationaldays (gd) 6 through gd 15 (rats) or gd 6 through gd 18 (rabbits)at analytically measured concentrations (as means ± SD)of 20.8 ± 0.90,41.1 ± 1.77, or 79.2 ± 10.8ppm; control animals were exposed to air alone. Monitors formaternal toxicity were body weight, food and water consumption,clinical signs, and hematology. At sacrifice (gd 2 1 rats, gd29 rabbits) maternal weight, liver weight, and gravid uterineweight were measured. Gestational parameters monitored werenumbers of corpora lutea, preimplantation losses, viable implants,early and late resorptions, and dead fetuses. Live fetuses weresexed, weighed, and examined for external, visceral, and skeletalmalformations and variations. Rabbit maternal toxicity occurredat 79.2 ppm as transient weight gain reduction during the exposureperiod. For maternal rats at 79.2 ppm, there were transientdecrease in body weight and body weight gain during exposure,reduced food consumption, increased water consumption, and excesslacrimation. At 41.1 ppm, maternal body weight gain was reducedduring the exposure period only. There were no treatment- relatedeffects with respect to hematology, necropsy, or gestationalparameters and no significant change in the incidence of malformationsor variations (expressed as total, individual. external, visceral.or skeletal). Thus, exposure of rats and rabbits to EGHE vaporduring the period of organogenesis produced maternal toxicityat near-saturation vapor concentrations (79.2 ppm), but no evidencefor developmental toxicity or teratogenicity. The no-effectvapor concentrations for maternal toxicity were 41.1 ppm forrabbits and 20.8 ppm for rats.     

Developmental Toxicity Evaluation of Inhaled Methyl Isobutyl Ketone in Fischer 344 Rats and CD-1 Mice

Developmental Toxicity Evaluation of Inhaled Methyl IsobutylKetone in Fischer 344 Rats and CD-1 Mice. Tyl, R. W., FRANCE,K. A., FISHER, L. C., PRITTS, I. M., TYLER, T. R., PHILLIPS,R. D., and MORAN, E. J. (1987). Fundam. Appl. Toxicol. 8, 310–327.Pregnant Fischer 344 rats and CD-1 mice were exposed to methylisobutyl ketone vapor (CAS No. 108-10-1) by inhalation on GestationalDays 6 through 15 at concentrations of 0, 300, 1000, or 3000ppm (mean analytical values of 0, 305, 1012, and 2997 ppm, respectively).The animals were sacrificed on Gestational Day 21 (rats) or18 (mice), and live fetuses were examined for external, visceral,and skeletal alterations. In rats, exposure to 3000 ppm resultedin maternal toxicity expressed as clinical signs, decreasedbody weight and body weight gain, increased relative kidneyweight, and decreased food consumption, and in fetotoxicityexpressed as reduced fetal body weight per litter and reductionsin skeletal ossification. In mice, exposure to 3000 ppm resultedin maternal toxicity expressed as exposure-related increasesin deaths (12.0%, 3/25 dams), clinical signs, and increasedabsolute and relative liver weight, and in fetotoxicity expressedas increased incidence of dead fetuses, reduced fetal body weightper litter, and reductions in skeletal ossification. No treatment-relatedincreases in embryotoxicity or fetal malformations were seenin either species at any exposure concentration tested. Therewas no evidence of treatment-related maternal, embryo, or fetaltoxicity (including malformations) at 1000 or 300 ppm in eitherSpecies.     

Evaluation of the Developmental Toxicity of {beta}-(3,4-Epoxycyclohexyl) ethytrimethosysilane in Fischer 344 Rats and New Zealand Whit Rabbits

Evaluation of the Developmental Toxicity of ß-(3,4-Epoxycyclohexyl)ethyltrimethoxysilanein Fischer 344 Rats and New Zealand White Rabbits. TYL, R. W.,BALLANTYNE, B., FISHER, L. C, AND FRANCE, K. A. (1988). FundamAppl Toxicol. 10, 439–452. ß-(3,4-epoxycyclohex-yl)ethyltrimethoxysilane(ECEMS, CAS No. 3388-04-3) is mutagenic in vitro and weaklycarcinogenic in mice after dermal application. Timed pregnantFischer 344 rats and New Zealand white rabbits were dosed withECEMS in corn oil by gavage on gestational days (gd) 6 through15 at doses of 0.0,0.25, 1.0, or 2.5 ml ECEMS/kg for rats and0.0,0.05,0.25, or 0.75 ml ECEMS/kg for rabbits. At terminationon gd 21 (rats) or gd 29 (rabbits), live fetuses were examinedfor external, visceral, and skeletal alterations. In rats, maternaltoxicity was observed at 1.0 and 2.5 ml/kg, as evidenced byreduced weight gain and food consumption during treatment, clinicalsigns of toxicity, reduced body weight on gd 21 (corrected forgravid uterine weight), and increased relative liver weight.There were no significant differences among groups on pre- orpostimplantation loss, fetal body weight/litter, or on the incidenceof malformations. Minimal fetal toxicity, dilated lateral cerebralventricles and reduced ossification in the forelimbs, was observedat 2.5 ml/kg. In rabbits, maternal mortality (2/20 does) andslightly (but statistically significantly) elevated maternalrelative kidney weight were observed at 0.75 ml/kg. Clinicalsigns of toxicity were observed at 0.25 and 0.75 ml/kg. Pre-and postimplantation loss, fetal body weight/litter, and theincidence of malformations were all unaffected by treatment.Minimal fetal toxicity, extra (13th) ribs and reduced ossificationin lumbar arch 4, was observed at 0.75 ml/kg ECEMS. Therefore,administration of ECEMS during organogenesis in rats and rabbitsproduced maternal toxicity at 1.0 and 2.5 ml/kg in rats andat 0.25 and 0.75 ml/kg in rabbits. Minimal fetal toxicity wasobserved at 2.5 ml/kg in rats and at 0.75 ml/kg in rabbits.No embryo-toxicity or teratogenicity was observed in eitherspecies at any dosage. The "no observable effect level" (NOEL)for maternal toxicity was 0.25 ml/kg for rats and 0.05 ml/kgfor rabbits; the NOEL for developmental toxicity was 1.0 ml7sol;kgfor rats and 0.25 ml/kg for rabbits.     

Hematopoietic effects in mice exposed to arsine gas

Arsine gas is a potent hemolytic agent. Concern about semiconductor workers prompted an in-depth study of arsine at the National Institute of Environmental Health Sciences to determine the hematopoietic effects of prolonged exposure to this gas. Female B6C3F1 mice were exposed by inhalation to 0, 0.5, 2.5, and 5 ppm arsine, 6 hr/day for 14 days. Body weights of exposed mice were comparable to those of controls, but a marked, concentration-related splenomegaly was observed. Higher level arsine exposure produced statistically significant decreases in red blood cells, hematocrit and hemoglobin, with increases in white blood cell counts and mean corpuscular volume of red blood cells. Erythropoiesis as measured by quantitation of erythroid precursors in culture revealed a marrow reduction of colony-forming unit erythroids/femur cells for all treated groups on Day 3 postexposure and only at the 5 ppm dose group on 24 days postexposure, while splenic erythropoiesis increased at higher concentrations of arsine. There was no alteration in bone marrow cellularity and a less significant effect on granulocyte-macrophage progenitors. A 12-week study of arsine at 0, 0.025, 0.5, and 2.5 ppm (6 hr/day) by inhalation showed similar effects on hematopoiesis in mice. In conclusion, arsine exposure at low concentrations produces a stress on the hematopoietic system characterized by hemolysis, which persists for a prolonged period following exposure.     

Developmental Toxicity Evaluation of Acrylamide in Rats and Mice

Developmental Toxicity Evaluation of Acrylamide in Rats andMice. FIELD, E. A., PRICE, C. J., SLEET, R. B., MARR, M. C,MORRISSEY, R. E., AND SCHWETZ, B. A. (1990). Fundam. Appl. Toxicol.14, 502–512. Acrylamide (ACRL), a widely used industrialchemical with neurotoxic effects, was evaluated for developmentaltoxicity. ACRL in distilled water was administered once dailyby gavage on gestational days (gd) 6–17 to mice (0, 3,15, or 45 mg/kg) and on gd 6–20 to rats (0, 2.5, 7.5,or 15 mg/kg). Following termination (gd 17, mice; gd 20, rats)fetuses were examined for external, visceral, and skeletal malformations.Maternal toxicity during treatment was observed at the highestdose as reduced body weight gain in both species and hindlimbsplaying in treated mice only. Weight gain corrected for graviduterine weight was also reduced in rats at 7.5 and 15 mg/kg/day.Embryo/fetal toxicity was not observed in rats, but fetal weightwas reduced in mice administered 45 mg/kg/day. No increase inthe incidence of malformations was observed in either species;however, the incidence of variations (predominately extra rib)increased with dose. In summary, administration of ACRL duringorganogene-sis produced maternal and developmental toxicityat 45 mg/kg/day in mice and maternal, but not developmental,toxicity at doses 7.5 mg/kg/day in rats.     

Developmental Toxicity of 2,3,4,7,8-Pentachlorodibenzofuran in the Fischer 344 Flat

Developmental Toxicity of 2,3,4,7,8-Pentachlordibenzofuran inthe Fischer 344 Rat. COUTURE, L. A,, HARRIS, M. W., AND BIRNBAUM,L. S. (1989). Fundam Appl Toxicol 12, 358–366. Fischer344 rats were exposed acutely to 2,3,4,7,8-pentachlordibenzofuran(4-PeCDF) during the organogenic period to evaluate its potentialas an inducer of teratogenic and embryolethal effects. All damswere treated by gavage with a single dose of 0, 30, 100, or300 µg 4- PeCDF/kg body wt on gestation Day (gd) 8, 10,or 12. An additional treatment group was included on gd 12 andadministered 10µg 4-PeCDF/kg body wt po. All animals werekilled on gd 20 and maternal and fetal toxicities were assessed.Determination of embryotoxicity involved both soft tissue andskeletal examinations. 4-PeCDF induced a dose-related decreasein corrected maternal weight gain following treatment on gd8 and 10, as well as resulted in a concomitant Increase in theliver/body weight ratios, first evident at 30 µg/kg forall 3 days of exposure. The maternal thymus weight decreasedrelative to body weight compared with those of controls. Embryo-fetaltoxicity was evident from the high mortality (>80%) observedat 300 µg/kg for all 3 days of exposure. Mean fetal weight,a sensitive indicator of fetal toxicity, decreased comparedto that of controls at 30, 100, and 300 µg/kg followingtreatment on either gd 8, 10, or 12. 4- PeCDF induced cleftpalate in survivors at a dose of 300 µg/kg for all 3 daysof exposure. In conclusion, 4-PeCDF is maternally and fetallytoxic regardless of the gestation day of exposure, but inducedterata only at doses where overt maternal and fetal toxicitywere observed, in contrast to previously reported studies inthe mice where teratogenic effects were observed at nonfetotoxicdose levels. Thus, the mouse may be a more sensitive model forevaluating specific toxic responses induced prenatally followingexposure to the structurally related polyhalogenated aromatichydrocarbons which include the dioxins, furans, biphenyls, andnaphthalenes.     

Hematological Responses to Arsine Exposure: Quantitation of Exposure Response in Mice

Hematological Responses to Arsine Exposure: Quantitation ofExposure Response in Mice. PETERSON, D. P., AND BHATTACHARYYA,M. H. (1985) Fundam. Appl. Toxicol. 5, 499–505. Hematologicalresponses of mice to arsine exposures for 1 hr at 5 to 26 partper million volume (ppmv) are described. Exposure concentrationsranged from a no-effect level for the endpoints studied (5 ppmv)to a concentration lethal to all mice in 4 days (26 ppmv). Hematocritvalues at 24 hr after exposure decreased linearly with increasingarsine concentration in the range 5 to 26 ppmv; the hematocritof the 26-ppmv group reached 10.5% at 24 hr, compared to 48.4%for control mice. Hematocrits of mice from all surviving groupswere at or slightly above control values by 11 days after exposure.Changes in numbers of erythrocytes paralleled changes in hematocrit.Significant increases in circulating reticulocytes occurredat 1 and 5 days after exposure; reticulocyte values returnedto control levels by 11 days after exposure. Changes in erythrocyteosmotic fragility were observed in mice exposed to 15 and 26ppmv arsine     

Developmental Toxicity Evaluation of Dietary Di(2-ethylhexyl) phthalate in Fischer 344 Rats and CD-1 Mice

Developmental Toxicity Evaluation of Dietary Di(2-ethylhexyl)phthalatein Fischer 344 Rats and CD-I Mice. TYL, R. W., PRICE, C. J.,MARR, M. C. AND KJMMEL, C. A. (1988). Fundam. Appl. Toxicol.10, 395–412. Di(2-ethylhexyl)phthalate (DEHP), a widelyused plasticizing agent, was evaluated for developmental toxicityin timed-pregnant Fischer 344 rats (22-25 dams/dose) and CD-Imice (24-30 dams/dose). DEHP was administered in the diet ongestational Days (gd) 0 through 20 at 0.0,0.5, 1.0, 1.5, or2.0% (rats) and on gd 0 through 17 at 0.00, 0.025,0.05, 0.10,or 0.15% (mice). At termination (gd 20, rats; gd 17 mice), allfetuses were examined for external, visceral, and skeletal malformationsand variations. In rats, maternal toxicity and reduced fetalbody weight per litter were observed at 1.0, 1.5, and 2.0%.Increased resorptions and decreased number of live fetuses/litterwere observed at 2.0%. Maternal food consumption was reducedand water consumption was increased in all DEHP groups. Thenumber and percentage of fetuses malformed per litter were unaffectedby treatment. In mice, maternal toxicity, increased resorptionsand late fetal deaths, decreased number of live fetuses, andreduced fetal body weight per litter were observed at 0.10 and0.15%. Maternal food and water consumption exhibited a dose-relatedupward trend with food consumption significantly increased at0.15%. The number and percentage of fetuses malformed per litter(open eye, exophthalmia, exen-cephaly, short, constricted, orno tail, major vessel malformations, fused or branched ribs,and fused or misaligned thoracic vertebral centra) were elevatedat 0.05,0.10, and 0.15% DEHP. In conclusion, DEHP was not teratogenicat any dose tested in Fischer 344 rats when administered inthe feed throughout gestation but did produce maternal and otherembryofetal toxicity at 1.0, 1.5, and 2.0%. In contrast, DEHPadministration throughout gestation in CD-I mice resulted inan increased incidence of malformations at doses which producedmaternal and other embryofetal toxicity (0.10 and 0.15%) andat a dose (0.057percnt;) which did not produce significant maternaltoxicity. No treatment-related embryofetal toxicity includingteratogenicity was observed in mice at 0.025% Or in rats at0.5% DEHP.     

The Developmental Toxicity of Orally Administered Oxytetracycline in Rats and Mice

The Developmental Toxicity of Orally Administered Oxytetracyclinein Rats and Mice. MORRISSEY, R.E., TYL, R.W., PRICE, C.J., LEDOUX,T.A., REEL, J.R., PASCHKE, L.L., MARR, M.C, AND KJMMEL, C.A.(1986). Fundam. Appl. Toxicol. 7, 434-443. Timed-pregnant CDrats and CD-1 mice were dosed by gavage with oxytetracyclinehydrochloride (OXT) in corn oil on gestational days (gd) 6-15(0, 1200, 1350, or 1500 mg/kg/day for rats; 0, 1325, 1670, or2100 mg/kg/day for mice). Deaths among treated females occurredin a dose-related manner in all OXT dose groups (2-7%, mice;5-24%, rats), but no maternal deaths occurred in the vehiclecontrol groups. Significant dose-related decreases in maternalweight gain during treatment, as well as for corrected gestationalweight gain (i.e., maternal gestational weight gain minus graviduterine weight), were observed at all doses in rats but notin mice. Gravid uterine weight was reduced in a dose-relatedmanner only in mice, with the high-dose group significantlyreduced compared to the control group. At termination (gd 20,rats; gd 17, mice), the status of uterine implantation siteswas recorded and live fetuses were weighed. Fetuses were examinedfor external, visceral, and skeletal abnormalities. There wereno significant effects of OXT in either species on the incidenceof postimplantation loss (resorptions plus dead fetuses) ormalformations. In both species, there was a significant trendtoward reduced fetal body weight, and each group of rats receivingOXT was significantly reduced compared to the control group.Administration of OXT during organogenesis at doses exceedingthe therapeutic range for humans produced maternal and fetaltoxicity, but did not produce any treatment-related increasein malformations.     

Developmental toxicity of 2,3,4,7,8-pentachlorodibenzofuran in the Fischer 344 rat

Fischer 344 rats were exposed acutely to 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) during the organogenic period to evaluate its potential as an inducer of teratogenic and embryolethal effects. All dams were treated by gavage with a single dose of 0, 30, 100, or 300 μg 4-PeCDF/kg body wt on gestation Day (gd) 8, 10, or 12. An additional treatment group was included on gd 12 and administered 10 μg 4-PeCDF/kg body wt po. All animals were killed on gd 20 and maternal and fetal toxicities were assessed. Determination of embryotoxicity involved both soft tissue and skeletal examinations. 4-PeCDF induced a dose-related decrease in corrected maternal weight gain following treatment on gd 8 and 10, as well as resulted in a concomitant increase in the liver/body weight ratios, first evident at 30 μg/kg for all 3 days of exposure. The maternal thymus weight decreased relative to body weight compared with those of controls. Embryo-fetal toxicity was evident from the high mortality (>80%) observed at 300 μg/kg for all 3 days of exposure. Mean fetal weight, a sensitive indicator of fetal toxicity, decreased compared to that of controls at 30, 100, and 300 μg/kg following treatment on either gd 8, 10, or 12. 4-PeCDF induced cleft palate in survivors at a dose of 300 μg/kg for all 3 days of exposure. In conclusion, 4-PeCDF is maternally and fetally toxic regardless of the gestation day of exposure, but induced terata only at doses where overt maternal and fetal toxicity were observed, in contrast to previously reported studies in the mice where teratogenic effects were observed at nonfetotoxic dose levels. Thus, the mouse may be a more sensitive model for evaluating specific toxic responses induced prenatally following exposure to the structurally related polyhalogenated aromatic hydrocarbons which include the dioxins, furans, biphenyls, and naphthalenes.     

Developmental toxicity study with 3-(methylthio)propionaldehyde vapor by whole-body exposure of Sprague-Dawley rats

Time-mated Sprague-Dawley rats were exposed whole body to analytically measured 3-(methylthio) propionaldehyde (3-MTP) vapor concentrations of 0 (air controls), 9.87, 58.3 and 127.8 ppm over gestational days (gd) 6-15 for 6 h day(-1). There was an exposure concentration-related maternal toxicity (clinical signs, body weight change and food consumption) that was marginal at 9.87 ppm. No effects on gestational parameters, fetal numbers and sex ratio or fetal body weights were noted. There was no increase in the incidence of either malformations or variations (total, external, visceral or skeletal). Thus, the no-observed-adverse-effect level (NOAEL) for development toxicity for exposure to 3-MTP vapor was 127.8 ppm.     

Developmental toxicity evaluation of inhaled tertiary amyl methyl ether in mice and rats

This evaluation was part of a much more comprehensive testing program to characterize the mammalian toxicity potential of the gasoline oxygenator additive tertiary amyl methyl ether (TAME), and was initiated upon a regulatory agency mandate. A developmental toxicity hazard identification study was conducted by TAME vapor inhalation exposure in two pregnant rodent species. Timed-pregnant CD(Sprague-Dawley) rats and CD-1 mice, 25 animals per group, inhaled TAME vapors containing 0, 250, 1500 or 3500 ppm for 6 h a day on gestational days 6-16 (mice) or 6-19 (rats). The developmental toxicity hazard potential was evaluated following the study design draft guidelines and end points proposed by the United States Environmental Protection Agency. Based on maternal body weight changes during pregnancy, the no-observable-adverse-effect level (NOAEL) was 250 ppm for maternal toxicity in rats and 1500 ppm for developmental toxicity in rats using the criterion of near-term fetal body weights. In mice, more profound developmental toxicity was present than in rats, at both 1500 and 3500 ppm. At the highest concentration, mouse litters revealed more late fetal deaths, significantly reduced fetal body weights per litter and increased incidences of cleft palate (classified as an external malformation), as well as enlarged lateral ventricles of the cerebrum (a visceral variation). At 1500 ppm, mouse fetuses also exhibited an increased incidence of cleft palate and the dam body weights were reduced. Therefore, the NOAEL for the mouse maternal and developmental toxicity was 250 ppm under the conditions of this study.     

Developmental toxicity evaluation of inhaled toluene diisocyanate vapor in CD rats.

Mated female CD (Sprague-Dawley) rats, 25/group, were exposed to toluene diisocyanate (TDI) vapor, for six h/day on gestational days (gd) 6 through 15, at 0.00, 0.02, 0.10, or 0.50 p.p.m.. Maternal clinical signs, body weights, and feed and water consumption were recorded throughout gestation. At termination (gd 21), maternal body, gravid uterine, and liver weights were recorded. Corpora lutea were counted, and implantation sites were identified: resorptions and dead and live fetuses. All live fetuses were examined for external alterations. One-half of the live fetuses/litter were examined for visceral (including craniofacial) alterations. The remaining intact fetuses/litter were stained with alizarin red S and examined for ossified skeletal alterations. Maternal toxicity at 0.50 ppm consisted of reduced body weights, body weight gains, feed consumption, and clinical signs of toxicity. Water consumption was unaffected. Gestational parameters exhibited no significant treatment-related changes, including pre- and postimplantation loss, sex ratio/litter, or fetal body weights/litter. Incidences of individual malformations, malformations by category (external, visceral, and skeletal), total malformations, individual external and visceral variations, variations by category, and total variations were unaffected. Of 111 skeletal variants observed, only 1, incidence of poorly ossified cervical centrum 5, was increased at 0.50 ppm, indicating possible minimal fetotoxicity, although it occurred in the absence of any other indications of developmental toxicity. Therefore, exposure to TDI vapor by inhalation, during major organogenesis in CD rats, resulted in maternal toxicity and minimal fetotoxicity at 0.50 ppm no observed adverse effect level (NOAEL) for maternal and developmental toxicity was 0.10 ppm. No treatment-related embryotoxicity or teratogenicity was observed.     

Reproductive and developmental toxicity of arsenic in rodents: a review

Arsenic is a recognized reproductive toxicant in humans and induces malformations, especially neural tube defects, in laboratory animals. Early studies showed that murine malformations occurred only when a high dose of inorganic arsenic was given by intravenous or intraperitoneal injection in early gestation. Oral gavage of inorganic arsenic at maternally toxic doses caused reduced fetal body weight and increased resorptions. Recently, arsenic reproductive and developmental toxicity has been studied in situations more similar to human exposures and using broader endpoints, such as behavioral changes and gene expression. For the general population, exposure to arsenic is mostly oral, particularly via drinking water, repeated and prolonged over time. In mice and rats, methylated or inorganic arsenic via drinking water or by repeated oral gavage induced male and female reproductive and developmental toxicities. Furthermore, at nonmaternally toxic levels, inorganic arsenic given to pregnant dams via drinking water affected fetal brain development and postnatal behaviors. However, arsenic given by repeated oral gavage to pregnant mice and rats was not morphologically teratogenic. In this review of arsenic reproductive and developmental toxicity in rats and mice, the authors summarize recent in vivo studies and discuss possible underlying mechanisms. The influences of folate, selenium, zinc, and arsenic methylation on arsenic reproductive and developmental toxicity are also discussed.     

Sequence of Toxic Events in Arsine-Induced Hemolysis in Vitro: Implications for the Mechanism of Toxicity in Human Erythrocytes

Arsine, the hydride of arsenic (AsH₃), is the most acutely toxicform of arsenic, causing rapid and severe hemolysis upon exposure.The mechanism of action is not known, and there are few detailedinvestigations of the toxicity in a controlled system. To examinearsine hemolysis and understand the importance of various toxicresponses, human erythrocytes were incubated with arsine invitro, and markers of toxicity were determined as a functionof time. The earliest indicators of damage were changes in sodiumand potassium levels. Within 5 min incubation with 1 mM arsine,the cells lost volume control, manifested by leakage of potassium,influx of sodium, and increases in hematocrit. Arsine did not,however, significantly alter ATP levels nor inhibit ATPases.These changes were followed by profound disturbances in membraneultrastructure (examined by light and electron microscopy).By 10 min, significant numbers of damaged cells formed, andtheir numbers increased over time. These events preceded hemolysis,which was not significant until 30 min. It has been proposedthat arsine interacts with hemoglobin to form toxic hemoglobinoxidation products, and this was also investigated as a potentialcause of hemolysis. Essentially on contact with arsine, methemoglobinwas formed but only reached 2–3% of the total cellularhemoglobin and remained unchanged for up to 90 min. There wasno evidence that further oxidation products (hemin and Heinzbodies) were formed in this system. Based on these observations,hemolysis appears to be dependent on membrane disruption bya mechanism other than hemoglobin oxidation.     

Modulation of glutathione and glutamate-L-cysteine ligase by methylmercury during mouse development.

The antioxidant tripeptide glutathione has been proposed to be important in defense against oxidative stress and heavy metal toxicity. We evaluated alterations in glutathione regulation and synthesis associated with low-level chronic methylmercury (MeHg) exposure in the developing mouse fetus. Female C57Bl/6 mice were given 0, 3, or 10 ppm MeHg in the drinking water for 2 weeks prior to breeding and throughout pregnancy. Fetuses were collected on gestational days (gd) 12 and 16. Total glutathione, reduced glutathione (GSH), oxidized glutathione (GSSR), and glutamate-L-cysteine ligase (Glcl) activity were assessed in yolk sacs and fetuses at gd 16. Western and Northern blots for Glcl-catalytic (Glclc) and Glcl-regulatory (Glclr) subunits were performed on gd 12 and gd 16 fetuses. There were no changes in total glutathione in gd 16 mouse fetuses with exposure, but there were dose-related decreases in GSH and increases in GSSR. In contrast, visceral yolk sacs exhibited an increase in total glutathione in the low-dose groups, but no changes in the high-dose group. There were no changes in Glcl activity in fetuses, but there was a 2-fold increase in Glcl activity in yolk sacs from both low-dose and high-dose groups. There was a 2-fold induction in GLCLC: mRNA and protein in the gd 16 yolk sacs at both 3 and 10 ppm MeHg. No treatment-related changes in Glclr protein in either gd 12 or gd 16 yolk sacs or fetuses were found. Thus, the yolk sac is capable of up-regulating Glclc and GSH synthetic capacity in response to MeHg exposure. This increase appears to be sufficient to resist MeHg-induced GSH depletion in the yolk sac; however fetal glutathione redox status is compromised with exposure to 10 ppm MeHg.     

Teratologic Evaluations of N,N-Diethyl-m-toluamide (DEET) in Rats and Rabbits

The potential for DEET to produce developmental toxicity wasevaluated in Charles River CD rats and New Zealand White rabbits.Rats were administered undiluted DEET by gavage on GestationalDays (gd) 6–15 at dosage levels of 0, 125, 250, and 750mg/kg/day. Rabbits were administered undiluted DEET by gavageon gd 6–18 at dosage levels of 0, 30, 100, and 325 mg/kg/day.Group sizes were 25 females per group for rats and 16 femalesper group for rabbits. Control rats and rabbits were ad ministeredcorn oil at the same dosage volumes administered in the high-doseDEET groups. In rats, maternal toxicity in the form of clinicalsigns including two deaths and depressed body weight and foodconsumption was observed at the high-dose level of 750 mg/kg/day.Rat fetal body weights per litter also were reduced at 750 mg/kg/day.In rabbits, maternal toxicity in the form of depressed bodyweight and food consumption was observed at the high-dose levelof 325 mg/kg/day. No maternal toxicity was observed at the low-or mid-dose groups for rats or rabbits. With the exception ofthe reduced fetal weights in rats at 750 mg/kg, there was noevidence of fetal toxicity, no effects on any of the gestationalparameters, nor were there any treat ment-related increasesin external, visceral, or skeletal variations or malformationsin the offspring from the rats and rabbits from these studies.1994 Society of Toxicology.     

Teratologic Evaluation of Dinitrotoluene in the Fischer 344 Rat

Teratologic Evaluation of Dinitrotoluene in the Fischer 344Rat. PRICE, C. J., TYL, R. W., MARKS, T. A., PASCHKE, L. L.,LEDOUX, T. A., AND REEL, J. R. (1985). Fundam. Appl. Toxicol..5,948-961. Technical grade dinitrotoluene (DNT) was administeredby gavage (po) to timed-pregnant Fischer 344 rats on GestationalDays (gd) 7 through 20. Mortality rates for the DNT (14, 35,37.5, 75, 100, or 150 mg/kg/day) groups were 4.5, 7.7, 0.0,0.0, 4.3, and 46.2% of treated females, respectively. No deathsoccurred in the positive control (hydroxyurea, 200 mg/kg/day)or vehicle control (com oil) groups. At sacrifice on gd 20,the hematological profile for dams in the 100-mg/kg/day groupexhibited characteristic signs of DNT toxicity. Treatment-relatedincreases in maternal relative liver and spleen weight (% bodyweight), and a dose-related decrease in absolute maternal weightgain during gestation (i.e., minus gravid uterine weight) wereobserved across all DNT groups. A notable increase in prenatalmortality occurred at the high dose (16.8% resorptions or latefetal deaths per litter for controls vs 49.6% for DNT), butdid not reach statistical significance. No statistically significanteffects on fetal growth or morphological development as a resultof DNT treatment were observed. Hydroxyurea produced mild hematoxicityin dams and fetuses. Effects of hydroxyurea on fetal growthand morphological development included decreased fetal bodyweight and crown-rump length, and an increased percentage ofmalformed fetuses (30% per litter). In conclusion, DNT was notfound to be teratogenic following oral administration to Fischer344 rats; embryo/fetal toxicity was observed only at a dosewhich also produced 46.2% maternal mortality.