Chronic Toxicity and Oncogenicity Inhalation Study with Vinyl Acetate in the Rat and Mouse

Vinyl acetate was evaluated for chronic toxicity and oncogenicityin male and female rats and mice in a 104-week study. Targetconcentrations were 0, 50, 200, and 600 ppm. The study includedinterim terminations at approximately 53 and 83 weeks and agroup whose exposure was terminated at 70 weeks and alloweda 15-week recovery period. Over the course of the exposures,body weight gain was consistently depressed in all 600 ppm groupsand in the 200 ppm mice. Except for female rats of the 600 ppmexposure group, recovery animals showed significant improvementsin weight gain relative to controls. There were no changes inhematological parameters of either species that could be unequivocallyrelated to treatment. The only effect noted on clinical chemicalparameters during the study were decreases in blood glucosein the 600 ppm females. There were no adverse effects on survivalin either species. Increases in lung weight were noted in ratsand mice primarily in the 600 ppm groups. These changes wereassociated with bronchial exfoliation, macrophage accumulation,and fibrous plaques and buds extending into the airway lumen,and bronchial/bronchiolar epithelial disorganization. The mostsignificant histopathological changes were noted in the nasalcavity. In the olfactory epithelium of both rats and mice, themain nonneoplastic changes included epithelial atrophy, regenerativeeffects (squamous metaplasia and respiratory metaplasia of olfactoryepithelium), basal cell hyperplasia, and epithelial nest-likeinfolds. No nonneoplastic changes were observed in the respiratoryepithelium of rats, while squamous metaplasia at the naso/maxilloturbinateregion was prevalent in mice. Nonneoplastic changes were similarin the recovery groups. Oncogenic responses to vinyl acetateexposure were mainly confined to the nasal cavity in rats andincluded endo- and exophytic papillomas, squamous cell carcinoma,carcinoma in situ in olfactory regions, and endophytic papillomain respiratory regions. Squamous cell carcinomas were also foundeither in areas normally covered by cuboidal epithelium or areasof unknown origin. One squamous cell carcinoma was found inthe larynx of a rat of the 600 ppm groups. One squamous cellcarcinoma was found in the lung of a mouse of the 600 ppm group.The no-observable- adverse-effect level for all effects was50 ppm in both species. The tumorigenic response appears tobe nonlinear. The nonlinear dose response and the unique natureof the rodent nasal cavity suggest that specific risk extrapolationmodels should be developed for vinyl acetate.     

Developmental Toxicity of Oral and Inhaled Vinyl Acetate in the Rat

Vinyl acetate (VA) is used almost exclusively as an industrialchemical in polymerization, copolymerization, or as a chemicalintermediate. The present studies were undertaken as part ofa collaborative effort by the VA producers of Western Europe,Japan, and the United States to provide animal toxicology datafor risk assessment. To assess the potential of VA causing developmentaltoxicity in rodents, groups of 23 or 24 Crl:CD(SD)BR rats weregiven 0, 200, 1000, or 5000 ppm VA in drinking water or exposed6 hr/day to 0, 50, 200, or 1000 ppm VA vapors on Days 6–15of gestation (both routes approximating 0, 25, 100, or 500 mg/kg/day).Administration of VA in the drinking water produced no evidenceof maternal or developmental toxicity. A significantly loweredwater intake was observed in dams from the 5000 ppm VA groupand probably reflected unpalatability of the VA water solutionat the highest dose level. In the inhalation study, maternaltoxicity was evident by a marked reduction in weight gain ofdams exposed to 1000 but not 200 or 50 ppm VA. Fetal toxicitywas evident by a statistically significant decrease in meanfetal weight and mean crown-rump length in fetuses from the1000-ppm VA group. In addition, there was a statistically significantincrease in the incidence of minor skeletal alterations in fetusesfrom dams exposed to 1000 ppm VA. Delayed ossification was themain skeletal alteration. In summary, pregnant rats were relativelyinsensitive to the effects of VA administered in the drinkingwater at a concentration level as high as 5000 ppm. However,VA did adversely affect both the dam and the conceptus at aninhaled concentration of 1000 ppm, but not at lower exposurelevels. These results indicate that VA is not uniquely toxicto the conceptus. The no-observed-effect level for the dam andconceptus under these experimental conditions was greater than5000 ppm for the drinking water study and was 200 ppm for theinhalation study.     

A Two-Generation Reproduction Study in Rats Receiving Drinking Water Containing Vinyl Acetate

Vinyl acetate (VA) is a commonly used chemical in polymerizationand copolymerization processes and as a chemical intermediate.As part of a collaborative effort between VA producers of theUnited States and British Petroleum, the present study was carriedout to provide a base set of data for risk assessment. Groupsof male and female Crl:CD(SD)BR rats were given 0, 200, 1000,or 5000 ppm VA via the drinking water over two generations.In addition, a cross-mating trial of control and 5000-ppm maleand female rats was conducted in the F₁ generation to investigatethe slightly decreased litter production in the high-dose group.No treatment-related mortality was observed in any of the groups.Water consumption was significantly reduced in the 5000-ppmgroups in both generations and in the 1000-ppm F₁, female rats.The body weights of the F₀ and F₁ male rats and the F₁, femalerats in the 5000-ppm group tended to be slightly lower thanthose of the control group. Body weight gain was significantlydecreased during lactation in the F₀ females at 5000 ppm andin the F₁, females at 1000 and 5000 ppm. Pup weights in theF₁, generation, but not in the F₂ generation, were significantlylower than those of the control on lactation Day 21. The numberof litters produced in the F₁ generation in the 5000-ppm groupwas slightly lower than that of the control group and was attributedto lower fertility. Fewer pups were produced when control femaleswere mated with the 5000-ppm males; however, the decrease wasdue to poor mating performance rather than decreased fertility.No decrease was apparent when the 5000-ppm females were matedwith the control group males. Under the conditions of this study,the no-observed adverse effort level was considered to be 1000ppm.     

Chronic Toxicity/Oncogenicity of Dimethylformamide in Rats and Mice Following Inhalation Exposure

The potential chronic toxicity and oncogenicity of dimethylformamide(DMF) was evaluated by exposing male and female rats and miceto 0, 25, 100, or 400 ppm DMF for 6 hr/day, 5 days/week for18 months (mice) or 2 years (rats). Clinical pathology was evaluatedat 3, 6, 12, 18, and 24 (rats only) months. An interim euthanasiafor rats occurred at 12 months and hepatic cell proliferationin rats and mice was examined at 2 weeks, 3 months, and 12 months.No compound-related effects on clinical observations or survivalwere observed. Body weights of rats exposed to 100 (males only)and 400 ppm were reduced. Conversely, body weights were increasedin 400 ppm mice. No hematologic changes were observed in eitherspecies. Serum sorbitol dehydrogenase activity was increasedin rats exposed to 100 or 400 ppm. There were no compound-relatedeffects on the estrous cycle of rats or mice at any concentration.Compound-related morphological changes were observed only inthe liver. In rats, exposure to 100 and 400 ppm produced increasedrelative liver weights, centrilobular hepatocellular hypertrophy,lipofuscin/hemosiderin accumulation in Kupifer cells, and centrilobularsingle cell necrosis (400 ppm only). In mice, increased liverweights (100 ppm males, 400 ppm both sexes), centrilobular hepatocellularhypertrophy, accumulation of lipofuscin/hemosiderin in Kupffercells, and centrilobular single cell necrosis were observedin all exposure groups. These observations occurred in a dose-responsefashion and were minimal at 25 ppm. No increase in hepatic cellproliferation was seen in mice or female rats. Slightly higherproliferation was seen in male rats exposed to 400 ppm at 2weeks and 3 months but not at 12 months. Dimethylformamide wasnot oncogenic under these experimental conditions in eitherthe rat or mouse.     

Chronic Toxicity/Oncogenicity of Dimethylacetamide in Rats and Mice Following Inhalation Exposure

The potential chronic toxicity and oncogenicity of dimethylacetamide(DMAC) was evaluated by exposing male and female rats and miceto 0, 25, 100, or 350 ppm DMAC for 6 hr/day, 5 days/week for18 months (mice) or 2 years (rats). Clinical pathology was evaluatedat 3, 6, 12, 18, and 24 (rats only) months. An interim euthanizationfor rats occurred at 12 months and hepatic cell proliferationin rats and mice was examined at 2 weeks and 3 and 12 months.No compound-related effects on survival were observed. Ratsexposed to 350 ppm had lower body weight and/or body weightgain. There were no compound-related effects on body weightor weight gain in mice at any concentration. There were no compound-relatedadverse effects on the incidence of clinical signs of toxicityin rats or mice. No hematologic changes were observed in eitherspecies. Serum sorbitol dehydrogenase activity was increasedin rats exposed to 350 ppm. Serum cholesterol and glucose concentrationswere significantly higher in 100 and 350 ppm female rats. Compound-relatedmorphological changes were observed in the liver. In rats, exposureto 100 or 350 ppm produced increased absolute and/or relativeliver weights, hepatic focal cystic degeneration, hepatic peliosis,biliary hyperplasia (350 ppm only), and lipofuscin/hemosiderinaccumulation in Kupffer cells. In mice, exposure to 100 or 350ppm produced increased absolute and relative liver weights (350ppm females only), accumulation of lipofuscin/hemosiderin inKupifer cells, and centrilobular single cell necrosis. Malerats exposed to 350 ppm also had significantly higher absoluteand relative kidney weights which correlated with the grossand microscopic changes resulting from a compound-related increasein severity of chronic progressive nephropathy. Female miceexposed to 350 ppm had an increased incidence of bilateral,diffuse retinal atrophy. No increase in hepatic cell proliferationwas seen in mice or rats at any exposure concentration. DMACwas not oncogenic under these experimental conditions in eitherthe rat or mouse. The NOAEL for male and female rats and miceis 25 ppm.     

Chronic Toxicity and Oncogenicity Study on Inhaled Vinylidene Chloride in Rats

Chronic Toxicity and Oncogenicity Study on Inhaled VinylideneChloride in Rats. QUAST, J. F., MCKENNA, M. J., RAMPY, L. W.,AND NORRIS, J. M. (1986). Fundam. Appl. Toxicol. 6, 105–144.Male and female Sprague—Dawley rats (Spartan substrain)were exposed to vinylidene chloride (VDC) by inhalation for18 months to assess chronic toxicity and oncogenic potentialof the subject test material. Interim sacrifices were performedat 1, 6, and 12 months. Rats were exposed to VDC concentrationsof 10 and 40 ppm for 6 hr/day, 5 days/week for the first 5 weeksof the study. Based upon the absence of observable treatment-relatedeffects among rats sacrificed after 1 month of exposure, theexposure concentrations were increased to 25 and 75 ppm VDC.Exposures were continued at these concentrations through the18th month of the study after which the surviving animals wereheld until 24 months and then sacrificed. Cytogenetic evaluationswere performed on a separate group of animals, four rats/sex,exposed to 0, 25, or 75 ppm VDC for 6 months. There were noexposure-related changes in the following parameters: mortality,appearance and demeanor, body weight data, clinical chemistrydeterminations, hematologic evaluations, urinalysis, or cytogeneticevaluation of bone marrow preparations. A target organ effect,characterized by hepatocellular fatty change in the midzonalregion of the hepatic lobule which was minimal in severity,was observed in both male and female rats of both the 25- and75-ppm exposure groups as early as the 6-month interim sacrifice.The midzonal fatty change was also observed at the 12-monthsacrifice but no indication of progression of this lesion ineither severity or incidence was apparent. During the last 6months of the study, after exposures had been discontinued,this effect was no longer discernible; therefore this alterationwas readily reversible. The incidences of several tumors and/ortumor types were statistically increased or decreased in VDC-exposedrats when compared to their respective control groups; noneof these differences were judged to be attributable to VDC exposure.     

A Three-Generation Rat Reproductive Toxicity Study of Vinylidene Chloride in the Drinking Water

A Three-Generation Rat Reproductive Toxicity Study of VinylideneChloride in the Drinking Water. Nitschke, K.D., Smith, F.A.,Quast, J.F., Norris, J.M. and Schwetz, B.A. (1983). Fundam.Appl. Toxicol. 3:75-79. A reproduction study was conducted withSprague-Dawley rats to evaluate the effects of parental exposurethrough three generations to drinking water containing 0, 50,100 or 200 ppm vinylidene chloride (VDC) on reproduction andthe development of the resultant offspring. A low fertilityrate was observed in three of the four groups including controls,for the fo generation rats. Remating the f₀ adults to producethe f_1b litters resulted in a lower fertility of dams ingesting200 ppm VDC than of dams ingesting 0, 50 or 100 ppm. However,the fertility index of the f₀ dams ingesting 200 ppm VDC inthe drinking water was higher for the f_1b litters than for thef_1a litters. No overall decrease in fertility was observed insubsequent matings to produce the f₂, f_3a, f_3b or f_3c litters.Although neonatal survival was decreased from concurrent controlvalues in the f₂ and f_3a litters of dams ingesting VDC in thedrinking water, the survival indices of the f₂ litters werewithin the range of control values for this strain of rat inthis laboratory. The apparent effect seen in the f₃. litterswas not repeated in subsequent matings of the same adults toproduce either the f_3b or the f_3c litters. Consequently, thedecreased survival observed in the f_3a was interpreted as beingdue to chance. Histopathologic examination of tissues of rats(f₁ and f₂ adults) exposed to vinylidene chloride in the drinkingwater in utero, during lactation, and post weaning revealedslight hepatocellular fatty change and an accentuated hepaticlobular pattern of a reversible nature in the adult rats. Inconclusion, ingestion of drinking water containing vinylidenechloride at concentrations which caused mild, dose-related changesin the liver, did not affect the reproductive capacity of ratsthrough three generations which produced six sets of litters.     

A Chronic Toxicity and Oncogenicity Study in Rats and Subchronic Toxicity Study in Dogs on Ingested Vinylidene Chloride

A Chronic Toxicity and Oncogenicity Study in Rats and a SubchronicToxicity Study in Dogs on Ingested Vinylidene Chloride. Quast,J.F., Humiston, C.G., Wade, C.E., Ballard, J., Beyer, J.E.,Schwetz, R.W. and Norris, J.M. (1983). Fundam. Appl. Toxicol.3:55-62. The chronic toxicity and oncogenic potential of ingestedvinylidene chloride (VDC) was evaluated in a 2-year study onSprague-Dawley rats and the subchronic toxicity was evaluatedin beagle dogs in a 97-day study. The vinylidene chloride wasincorporated in the drinking water of the rats at nominal concentrationsof 50, 100 or 200 ppm. The time weighted average mg/kg bodyweight/day dosages of vinylidene chloride administered to themale and female rats over the 2-year period at the various meananalyzed concentrations were 7, 10 or 20 for the males and 9,14 or 30 for the females. Dogs were administered vinylidenechloride in peanut oil incorporated in a gelatin capsule atconcentrations which provided 6.25, 12.5 or 25 mg vinylidenechloride/kg body weight/day. There were no significant differencesbetween the groups of rats or dogs ingesting vinylidene chlorideand their corresponding control groups in the following parameters:appearance and demeanor, mortality, body weight, food consumption,hematology, urinalysis, clinical chemistry determinations, organweights and organ to body weight ratios. There were no significantdifferences in water consumption of the groups of rats ingestingvinylidene chloride and the controls. The sole treatment-relatedobservation in the rats, evident only upon microscopic examination,was in the liver. The observation was characterized by a minimalamount of hepatocellular swelling with midzonal fatty changewhich occurred in the females at all dose levels and in themales only at the 200 ppm level. No exposure-related neoplasticchanges occurred in the rats in any of the test groups. No exposure-relatedgross or histopathological changes were present in the tissuestaken from the dogs at the termination of the 97-day study.     

Toxicity of Calcium Sodium Metaphosphate Fiber: II. Chronic Inhalation and Oncogenicity Study

Male and female Fischer 344 rats (80/sex/group) were exposedto CSM fiber 6 hr/day, 5 days/week at target-exposure levelsof 0, 1, 5, or 25 mg/m³ for 24 months, corresponding to 0, 27,80, and 513 fibers/cc, respectively. Number and size of theairborne fibers were determined during the course of the study.At 3 and 12 months, 10 rats/sex/group were euthanized and at18 and 24 months 5 rats/sex/group were euthanized. In addition,5 rats/ sex/group were removed from exposure at 18 months andmaintained for a 6-month recovery period. All animals survivingat the completion of the exposure period were maintained ina clean environment for up to 5 additional months. Clinicallaboratory examinations were performed on 10 animals/sex/groupat 3, 12, and 24 months. The number of fibers in the lung werealso determined at 3, 12, 18, and 24 months. Body weight andsurvival did not appear to be affected by treatment. There wereno biologically significant effects on clinical parameters.There was a dose-related increase in lung weight during theexposure period which was generally reversible during the recoveryperiods. There also was a dose-related increase in the numberof fibers/ milligram of lung, but no increase in lung fiberburden after the first 3 months. The number of fibers in thelungs of animals exposed to CSM fiber for 18 months and allowed6-month recovery period showed a decrease especially at thehigh dose. No increase in tumors (benign or malignant) was observedin this study. Microscopic changes considered reflective ofan irritant response were observed in the nasal turbinates notablyat the 5 and 25 mg/m³ levels. Histological changes were alsoobserved in the lungs at the 5 and 25 mg/m³ levels. The incidenceand/ or severity of histopathological changes in the 1 mg/m³group was considered to be essentially comparable to controls.     

Chronic Toxicity and Three-Generation Reproduction Study of Styrene Monomer in the Drinking Water of Rats

Chronic Toxicity and Three-Generation Reproduction Study ofStyrene Monomer in the Drinking Water of Rats. BELILES, R. P.,BUTALA, J. H., STACK, C. R., AND MAKRIS, S. (1985). Fundam.Appl. Toxicol.. 5,855-868. Chronic toxicity and reproductiveperformance were evaluated in groups of rats receiving styrenemonomer in their drinking water at nominal concentrations of0, 125, or 250 ppm. Fifty male and 70 female rats in each testgroup and 76 males and 104 females in the control group wereplaced on a 2-year study and followed for observations of generalhealth which included measurement of body weight, food and waterconsumption, hemograms, clinical chemistries, urinalysis, andhistopathological examination. Ten males and 20 females fromeach group in the study were mated to produce F₁ pups. Thesepups were subsequently mated to produce three generations ofoffspring, all maintained on styrene-treated drinking water.For each generation, the following were evaluated: fertility,litter size, pup viability, pup survival, sex ratio, pup bodyweight, weanling liver and kidney weight, and marrow cytogenetics.Except for a statistically significant reduction in water consumptionfor styrene-treated rats, no treatment-related changes, includingmortality patterns, were reported for animals in the chronicstudy. The data evaluated for reproductive performance alsoshowed no evidence of styrene-related changes. It was concludedthat the administration of styrene in the drinking water ofrats for 2 years produced no deleterious dose-related effectsor decrements in reproductive performance.     

Trimethylphosphate: A 30-Month Chronic Toxicity/Carcinogenicity Study in Wistar Rats with Administration in Drinking Water

Trimethylphosphate (TMPO) was administered to 50 male and 50female Wistar rats through their drinking water at doses of0, 1, 10, or 100 mg/kg body weight up to 30 months. The dosageof 100 mg/kg was reduced to 50 mg/kg in week 54 for reasonsof tolerance, and the animals were euthanized in week 100. Additional10 animals per dose and sex were treated for 12 months and theneuthanized for interim analysis. Weakness of the hind limbs,increased incidences of sunken flanks, distended abdomen, andpoor general condition were observed in both sexes of the 100/50mg/kg group beginning with week 46. Food intake was reducedin high dose males. At 10 mg/kg body weights were up to 10%(males) and at 100/50 mg/kg up to 20% (males) or 15% (females)lower than in controls. Mortality was not affected in animalsreceiving up to 10 mg/kg. At 100/50 mg/kg it was markedly increased,reaching about 70% at week 100. Relatively slight hematologicchanges (reduced hemoglobin, hematocrit, erythrocyte counts,increased reticulocyte numbers, and thrombocyte counts as wellas a shift in the differential blood count) at 100/50 mg/kgare interpreted as changes most probably secondary to the othertoxic effects. Increased cholesterol concentrations in plasma,shifts in the serum protein electrophoresis (males), increasedorgan weights (females), and an increased incidence of necrosesand lymphocytic infiltrations point to a treatment-related effecton the liver at 100/50 mg/kg. Slightly increased protein excretion,increased relative kidney weights, and an increased incidenceof chronic progressive nephropathy are considered treatment-relatedbut rather secondary effects at 100/50 mg/kg. At 100/50 mg/kgan increased incidence and severity of bilateral tubular atrophyin the testes was diagnosed. The most important toxic effectwas neurotoxicity, consisting of degeneration and loss of nervefibers in the peripheral nerves and the spinal cord, associatedwith myopathic changes, and occurring at 100/50 mg/kg. The no-observed-adverse-effect-level,based on the suppression of body weight gain, is 1 mg/kg inmales and 10 mg/kg in females. The incidence, time of occurrence,spectrum of types, and localizations of tumors provided no indicationof a tumorigenic/carcinogenic effect of the test substance.TMPO is therefore considered not to be carcinogenic in Wistarrats.     

Chronic Toxicity and Oncogenicity Studies of Ethylene Glycol in Rats and Mice

Chronic Toxicity and Oncogenicity Studies of Ethylene Glycolin Rats and Mice. DEPASS, L.R., GARMAN, R.H., WOODSIDE, M.D.,GIDDENS, W.E., MARONPOT, R.R., AND WEIL, C.S. (1986). Fundam.Appl. Toxicol. 7, 547-565. These studies were performed to assessthe chronic toxicity and oncogenicity of ethylene glycol (EG)in rats and mice. Groups of 130 Fischer 344 rats and 80 CD-Imice per sex were fed diets yielding approximate dosages of1.0, 0.2, or 0.04 g/kg/day of EG. Two separate control groupsin each study received no EG. Mortality rate was increased inhigh-dose male rats all of which died by 475 days. The followingeffects were also observed in high dose male rats: reduced bodyweight gain, increased water intake, increased blood urea nitrogenand creatinine, reduced erythrocyte count, reduced hematocritand hemoglobin, increased neutrophil count, increased urinevolume, reduced specific gravity and pH. Urinary calcium oxalatecrystals and increased kidney weight were seen in all high-doserats. Uric acid crystals were seen in the urine of high-dosefemale rats at 18 and 24 months. Histopath-ologic changes inhigh-dose male rats included tubular cell hyperplasia, tubulardilation, peritu-bular nephritis, parathyroid hyperplasia, andgeneralized soft tissue mineralization. Fatty change of theliver was seen in high- and intermediate-dose female rats. Noclinical signs, or gross or microscopic evidence of toxicitywas seen in mice at the dosages used. Water intake and clinicalpathologic parameters were not measured in the mouse study.In these studies there was no evidence of an oncogenic effectof EG in rodents.     

Inhalation Oncogenicity Bioassay in Rats and Mice with Vinyl Fluoride

The purpose of this study was to assess the oncogenic potentialof vinyl fluoride in rats and mice when administered by inhalation.Male and female rats and mice were exposed to 0, 25, 250, or2500 ppm vinyl fluoride 6 hr per day, 5 days per week, for 2years (rats) or 18 months (mice). Slight body weight gain decrementswere noted in groups of vinyl fluoride-exposed rats and mice.No significant clinical signs of toxicity were noted other thanan increase in the incidence of palpable masses in the regionof the mammary gland in female mice exposed to vinyl fluoride.Survival was decreased in male rats and mice of the 250 and2500 ppm groups and female rats and mice of all vinyl fluoride-exposedgroups compared to controls. Urinary fluoride excretion, anindicator of vinyl fluoride metabolism, increased with concentrationand time although the dose relationship appeared to plateauat concentrations 250 ppm. Gross observations made at necropsyof rats supported histological observations of hepatic hemangiosarcoma,hepatocellular adenoma and carcinoma, hepatic foci of clearcell and basophilic alteration, hepatic sinusoidal dilatation,metastatic lung tumors, and Zymbal's gland tumors. Hepatic hemangiosarcomawas the sentinel lesion in rats. Gross observations made atnecropsy of mice supported histological observations of bronchioloalveolaradenoma and hyperplasia, hepatic hemangiosarcoma and hepatocellularhyperplasia with angiectasis and peliosis, and mammary glandadenocarcinoma and hyperplasia. Bronchioloalveolar adenoma appearedto be the sentinel lesion in mice. The spectrum of vinyl fluoride-inducedtumors is similar to that induced by other monohaloethylenesin rats and mice. Under the conditions of this study, vinylfluoride was carcinogenic in male and female rats and mice atconcentrations greater than or equal to 25 ppm.     

Chronic Toxicity and Oncogenicity Bioassay of Inhaled Toluene in Fischer-344 Rats

Chronic Toxicity and Oncogenicity Bioassay of Inhaled Toluenein Fischer-344 Rats. Gibson, J.E. and Hardisty, J.F. (1983).Fundam.Appl. Toxicol. 3: 315–319. The chronic toxicity and oncogenicityof inhaled toluene were assessed in Fischer-344 rats. One hundredand twenty animals of each sex were exposed for 6 hours/day,5 days/week, for up to 24 months at concentrations of toluenein air of 0, 30, 100, or 300 ppm. The calculated time-weightedaverage concentrations for the 24 months of exposure were 0.0,30.1, 99.7, and 299.0 ppm, respectively. Interim sacrificeson randomly selected animals were conducted after 6, 12 and18 months of exposure. All surviving rats were sacrificed at24 months. A large battery of tissues and organs from all animalsin the control and 300 ppm toluene group were examined for histopathology.All animals were examined for clinical changes throughout thecourse of the study and selected animals were used to determineophthalmologic, hematologic, clinical blood chemistry or urihalysiseffects. There were 140 unscheduled deaths over the 2-year study.Gross pathologic examination of rats dying during the courseof the study, or that were sacrificed as scheduled, did notreveal any lesions attributable to toluene exposure. Histologically,a variety of proliferative, degenerative and inflammatory lesionswere observed in the control and 300 ppm toluene-exposed group.These lesions were considered unrelated to toluene exposure.The results provide no evidence that toluene causes chronictoxicity or incogenicity in Fischer-344 rats at these concentrations.     

In Utero Exposure to Opioids: An Observational Study of Mothers Involved in the Child Welfare System

Background: Women are underrepresented in the current substance abuse research; however, women are a particularly vulnerable population when it comes to opioid use and abuse. Pregnant women are even more so, because of the potential that exists for in utero exposure (IUE) to substances. Objectives: To identify trends in IUE to opioids in order to ensure that resources are allocated effectively to address the current opioid epidemic and to assist the populations most affected by it. Methods: This study draws on 15 years' worth of clinical assessment data collected from 3598 child welfare-involved mothers to assess for trends in IUE to substances over time. Data from the last 5 year period (N = 852) are then analyzed to identify recent demographic correlates associated with IUE to opioid substances. Results: A substantial increase in the rates of IUE to opioids over the past 15 years is observed among child welfare-involved mothers. Moreover, we find that race is a significant correlate of IUE to opioids. Conclusion: Study findings are consistent with other recent research that demonstrates racial differences in the populations that are most affected by the opioid epidemic; however, more research is needed to determine how these racial differences in rates of IUE to opioids affect child welfare outcomes.     

Ochratoxin A: In Utero Exposure in Mice Induces Adducts in Testicular DNA

Ochratoxin A (OTA) is a nephrotoxin and carcinogen that is associated with Balkan endemic nephropathy and urinary tract tumors. OTA crosses the placenta and causes adducts in the liver and kidney DNA of newborns. Because the testis and kidney develop from the same embryonic tissue, we reasoned that OTA also may cause adducts transplacentally in the testis. We tested the hypothesis that acute exposure to OTA, via food and via exposure in utero, causes adducts in testicular DNA and that these lesions are identical to those that can be produced in the kidney and testis by the consumption of OTA. Adult mice received a single dose of OTA (from 0–1,056 µg/kg) by gavage. Pregnant mice received a single i.p. injection of OTA (2.5 mg/kg) at gestation day 17. DNA adducts were determined by ³²P-postlabeling. Gavage-fed animals sacrificed after 48 hours accumulated OTA in kidney and testis and showed DNA adducts in kidney and testis. Some OTA metabolites isolated from the tissues were similar in both organs (kidney and testis). The litters of mice exposed prenatally to OTA showed no signs of overt toxicity. However, newborn and 1-month old males had DNA adducts in kidney and testis that were chromatographically similar to DNA adducts observed in the kidney and testis of gavage-fed adults. One adduct was identified previously as C8-dG-OTA adduct by LC MS/MS. No adducts were observed in males from dams not exposed to OTA. Our findings that in utero exposure to OTA causes adducts in the testicular DNA of male offspring support a possible role for OTA in testicular cancer.     

The Chronic Toxicity and Oncogenicity of Inhaled Technical-Grade 1,3-Dichloropropene in Rats and Mice

The Chronic Toxicity and Oncogenicity of Inhaled Technical-Grade1,3-Dichloropropene in Rats and Mice. LOMAX, L, G., STOTT, W.T., JOHNSON, K. A., CALHOUN, L. L., YANO, B. L., AND QUAST,J. F. (1989). Fundam. Appl. Toxicol. 12, 418–431. Maleand female Fischer 344 rats and B6C3F1 mice were exposed byinhalation to target concentrations of 0, 5, 20, or 60 ppm (0,22.7, 90.8, or 272 mg/m³) technical-grade 1,3-dichloropropene(DCPT) 6 hr/day, 5 days/week, for upto 2 years. Ancillary groupsof rats and mice were exposed for 6- and 12- month periods.Significant treatment-related nonneoplastic changes followingexposure for 2 years were morphological alterations in the nasaltissues of rats exposed to 60 ppm and mice exposed to 20 or60 ppm DCPT. In addition, mice exposed to 20 or 60 ppm had hyperplasiaof the transitional epithelium lining the urinary bladder. Survivalof male and female rats and mice exposed to DCPT was similarto that of the corresponding controls. No statistically increasedtumor incidence was observed in treated rats. The only neoplasticresponse observed in mice was an increased incidence of benignlung tumors (bronchioloalveolar adenomas) in male mice exposedto 60 ppm DCPT (22/50 versus 9/50 in controls).     

Methylene Chloride: A 2-Year Inhalation Toxicity and Oncogenicity Study in Rats

Methylene Chloride: A 2-Year Inhalation Toxicity and OncogenicityStudy in Rats. Nit-schke, K. D. Burek, J. D., Bell, T. J., Kociba,R. J., Rampy, L. W. and McKenna, M. J. (1988). Fundam. Appl.Toxicol. 11, 48-59. Male and female Sprague-Dawley rats wereexposed to 0, 50, 200, or 500 ppm methylene chloride for 6 hr/day,5 days/week for 2 years. Blood carboxyhemoglobin levels wereelevated in a dose-dependent (less than linear) manner in ratsexposed to 50–500 ppm methylene chloride Histopathologiclesions related to methylene chloride exposure were confinedto the liver and mammary tissue of rats. An increased incidenceof hepatocellular vacuolization was observed in male and femalerats exposed to 500 ppm methylene chloride. Female rats exposedto 500 ppm methylene chloride also had an increased incidenceof multinucleated hepatocytes and number of spontaneous benignmammary tumors/ tumor-bearing rat (adenomas, fibromas, and fibroadenomaswith no progression toward malignancy); the incidence of benignmammary tumors in female rats exposed to 50 or 200 ppm methylenechloride was comparable to historical control values. No increasein the number of any malignant tumor type was observed in ratsexposed to concentrations as high as 500 ppm methylene chloride.Additional groups of female rats were exposed to 500 ppm methylenechloride for the first 12 months or the last 12 months of the24-month study. The response observed in female rats exposedto 500 ppm for the first 12 months was the same as that observedin female rats exposed to 500 ppm for 2 years. Conversely, theresponse observed in female rats exposed to 500 ppm during thelast 12 months of the study was similar to that observed incontrol animals. Based upon the results of this study, the no-adverse-effectlevel for chronic inhalation exposure of Sprague-Dawley ratswas judged to be 200 ppm methylene chloride.     

Methylene Chloride: A Two-Year Inhalation Toxicity and Oncogenicity Study in Rats and Hamsters

Methylene Chloride: A Two-Year Inhalation Toxicity and OncogenicityStudy in Rats and Hamsters. BUREK, J. D., NITSCHKE, K. D., BELL,T. J., WACKERLE, D. L., CHILDS, R. C., BEYER, J. E., DITTENBER,D. A., RAMPY, L. W., AND MCKENNA, M. J. (1984). Fundam. Appl.Toxicol. 4, 30–47. A long-term study was conducted todetermine the possible chronic toxicity and oncogenicity ofmethylene chloride. Rats and hamsters were exposed by inhalationto 0, 500, 1500, or 3500 ppm of methylene chloride for 6 hrper day, 5 days a week, for 2 years. No exposure-related cytogeneticeffects were present in male or female rats exposed to 500,1500, or 3500 ppm. Females rats exposed to 3500 ppm had an increasedmortality rate while female hamsters exposed to 1500 or 3500ppm had decreased mortality rates. Carboxyhemoglobin valueswere elevated in rats and hamsters exposed to 500, 1500, or3500 ppm with the percentage increase in hamsters greater thanin rats. Minimal histopathologic effects were present in thelivers of rats exposed to 500, 1500, or 3500 ppm. Decreasedamyloidosis was observed in the liver and other organs in hamstersexposed to 500, 1500, or 3500 ppm. While the number of femalerats with a benign tumor was not increased, the total numberof benign mammary tumors was increased in female rats in anexposure-related manner. This effect was also evident in malerats in the 1500- and 3500-ppm exposure groups. Finally, malerats exposed to 1500 or 3500 ppm had an increased number ofsarcomas in the ventral neck region located in or around thesalivary glands. Therefore, in this 2-year study, some effectswere observed in male and female rats exposed to 500, 1500,or 3500 ppm of methylene chloride. In contrast, hamsters exposedto the same exposure concentrations had less extensive spontaneousgeriatric changes, decreased mortality (females), and lackedevidence of definite target organ toxicity.     

In Utero and Lactational Exposure to Fluoxetine in Wistar Rats: Pregnancy Outcomes and Sexual Development

This study evaluated the reproductive effects of fluoxetine exposure in utero and during lactation on pregnancy outcomes and the sexual development of offspring. Pregnant Wistar rats were treated daily with fluoxetine (0.4, 1.7 and 17 mg/kg/day) or distilled water by gavage from gestation day (GD) 7 to lactation day (LD) 21. A significant reduction in maternal body weight was observed during pregnancy and lactation in dams exposed to 17 mg/kg fluoxetine. Hormone analysis revealed an increase in progestagen and glucocorticoid metabolites on GD 15 and oestrogen and progestagen metabolites on LD 7 in dams treated with 17 mg/kg fluoxetine. Oestrogen metabolites also were increased on LD 7 in dams treated with 0.4 mg/kg fluoxetine. Besides that, an increase in the weight of the adrenal glands and a reduction in uterine weight in dams exposed to highest dose of fluoxetine were observed. Finally, pup birthweight and the viability and weaning indices also were reduced in animals exposed to 17 mg/kg fluoxetine. Overall, maternal hormonal changes were only observed at the highest dose tested, which also induced maternal and foetal toxicity. No significant changes were seen in dams or offspring exposed to therapeutic‐like doses.