Chronic Inhalation Toxicity and Carcinogenicity Study of Respirable Polymeric Methylene Diphenyl Diisocyanate (Polymeric MDI) Aerosol in Rats

Four groups of 60 Wistar rats of each sex were exposed by inhalationto 0, 0.2, 1.0, or 6.0 mg/m³ respirable polymeric methylenediphenyl diisocyanate (polymeric MDI) aerosol (93.5% < 4.2µm)for 6 hr a day, 5 days a week for up to 24 months. In addition,satellite groups of 10 rats/sex/group received the same treatmentfor 12 months. There was no adverse effect on general health,survival, body weight, or hematological or clinical chemistryparameters. Lung weights were increased in both males and femalesexposed to 6.0 mg polymeric MDI/m³ for 12 or 24 months. Grossexamination at autopsy of males exposed to 6.0 mg polymericMDI/m³ for 24 months revealed an increased incidence of spottedand discolored lungs. Increased incidences of degeneration andbasal cell hyperplasia of the nasal olfactory epithelium, oftenaccompanied by hyperplasia of Bowman's glands, were found inthe 1.0 and 6.0 mg/m³ groups. Light and electron microscopicstudies of the lungs revealed accumulations of alveolar macrophagescontaining polymeric MDI-associated refractile yellowish materialat the level of the alveolar duct in all exposed groups. Alveolarduct epithelialization as well as fibrosis of tissues surroundingthe macro phage accumulations occurred at the 1.0 and 6.0 mg/m³exposure levels. In addition, increased incidences of calcareousdeposits and localized alveolar bronchiolization were seen inthe 6.0 mg/m³ group. Moreover, eight pulmonary adenomas (sixin males and two in females) and one pulmonary adenocarcinoma(in a male) were observed in the 6.0 mg/m³ exposure group. Thetime sequence of the spectrum of pulmonary changes indicatesthat recurrent alveolar wall damage by polymeric MDI and/orpolymeric MDI-containing alveolar macrophages leads to alveolarbronchiolization and ultimately to bronchioloalveolar tumors.No lung tumors were found in the lower concentration groupsand in the control group. The incidence and distribution ofother types of tumors were not influenced by polymeric MDI.It was concluded that in the present study, the "no-observed-adverse-effectlevel" of polymeric MDI was 0.2 mg/m³ and that chronic exposureto polymeric MDI at a level of 6.0 mg/m³ was related to theoccurrence of pulmonary tumors. It was also concluded that exposureto polymeric MDI at concentrations not leading to recurrentlung tissue damage will not produce pulmonary tumors.     

Inhalation Carcinogenicity and Chronic Toxicity of Carbon Tetrachloride in Rats and Mice

Carcinogenicity and chronic toxicity of carbon tetrachloride were examined by inhalation exposure of 50 F344 rats and 50 BDF1 mice of both sexes to carbon tetrachloride at 0 (clean air), 5, 25, or 125 ppm (v/v) for 6 h/day, 5 days/wk, for 104 wk. Incidences of hepatocellular adenomas and carcinomas in rats and mice of both sexes and of adrenal pheochromocytomas in mice of both sexes were significantly increased dose-dependently. Hepatocellular carcinomas and cirrhosis significantly occurred in the 125-ppm-exposed rats of both sexes, and 3 cases of hepatocellular carcinomas and increased incidences of hepatic altered cell foci were noted in the 25-ppm-exposed female rats. Hepatocellular carcinomas were induced in mice of both sexes at 25 and 125 ppm, and hepatocellular adenomas occurred in females at 5 ppm without any degenerative or necrotic change in hepatocytes. Hepatocellular carcinomas metastasized to the lung. The chronic hepatotoxicity was characterized by cirrhosis, fibrosis, and fatty change in rats, and ceroid deposition, bile-duct proliferation, and hydropic change in mice. Survival rates were decreased in the 125-ppm-exposed rats and mice of both sexes and in the 25-ppm-exposed female mice, in association with decreased body weights. The decreased survival rates were considered to be causally related to both various tumors including hepatocellular carcinomas and severe chronic progressive nephropathy in rats and to hepatocellular carcinomas in mice. This study provided clear evidence of carcinogenicity for carbon tetrachloride in rats and mice. A cytotoxic-proliferative and genotoxic mode of action for carbon tetrachloride-induced hepatocarcinogenesis was suggested.     

Chronic Inhalation Toxicity and Carcinogenicity Study on Potassium Octatitanate Fibers (TISMO) in Rats

A chronic inhalation toxicity/carcinogenicity study of potassium octatitanate fibers (TISMO) was conducted in male Fischer 344 rats. Groups of 135 rats were exposed via whole-body inhalation to 0, 20, 60, or 200 WHO fibers/cc of TISMO, 6 h/day, 5 days/w for 24 mo. Six of 30 subgroup rats were killed after 3, 6, 12, 18, and 24 mo of exposure for lung burden evaluations. Another 30 subgroup rats were removed from the exposure chambers after 6 mo of exposure, placed in clean air, and from this group 6 rats were killed at 3, 6, 9, 12, and 18 mo later to study lung clearance. The remaining 75 rats in each group were subjected to 24 mo of exposure for chronic toxicity and carcinogenicity study. Rats exposed to HEPA-filtered air (chamber control) were used as a negative control in each study. The lung burden results indicated that a time point of equilibrium between lung burden and lung clearance at 20 WHO fibers/cc exposure was attained after approximately 18 mo of exposure. There was no difference in the number of WHO fiber from the lungs between 18 and 24 mo at 20 WHO fibers/cc exposure. But disproportional rapid increase in lung burden at 200 WHO fibers/cc exposure appeared to be saturation of lung clearance mechanism resulting from lung overloading. At 200 WHO fibers/cc exposure, approximately 22.9 and 70.5 million WHO fibers were retained in the lung after 3 and 6 mo of exposure, respectively, but lungs revealed normal in appearance. However, alveolar walls enclosing aggregated TISMO-laden alveolar macrophages (AMs) showed fibrotic thickening and approximately 197.3 million WHO fibers were retained in the lungs after 18 mo of exposure. Inhaled fibers were rapidly cleared during 3- and 6-mo recovery periods, and thereafter gradually progressive fiber reduction was observed throughout 18 mo of recovery. The number of WHO fibers decreased by approximately 72%, 74%, and 79% in the 200, 60, and 20 WHO fibers/cc groups, respectively, at the end of the 18-mo recovery period following 6 mo of exposure. Although inhaled TISMO fibers in the 20 WHO fibers/cc exposure group were phagocytized by alveolar macrophages (AMs) the lung morphology appeared normal throughout 24 mo of exposure. At 60 WHO fibers/cc exposure, a slight dose- and time-dependent increase in TISMO-laden AMs was observed throughout 3, 6, and 12 mo of exposure and some alveoli containing aggregated TISMO-laden AMs showed alveolar wall thickening at 18 mo of exposure and minimal alveolar fibrosis at 24 mo of exposure. The exposure concentration is interpreted as a borderline effect level. At 200 WHO fibers/cc exposure, lungs preserved normal architecture at 3 and 6 mo of exposure. Some alveolar walls enclosing aggregates of TISMO-laden AMs were slightly thickened after 12 mo of exposure and revealed slight alveolar fibrosis after 18 and 24 mo of exposure. Neither exposure related-pulmonary neoplasm nor mesothelioma was observed in 24 mo of exposure. The 20 WHO fibers/cc exposure concentration is considered to be a no-observable-adverse-effect level (NOAEL). TISMO exposure limits of 1 WHO fiber/cc would not impose a significant health hazard to humans in the workplace based on the animal experiments and medical surveys on workers.     

Chronic Inhalation Toxicity/Carcinogenicity Study in Rats Exposed to Fluorocarbon 113 (FC-113)

Chronic Inhalation Toxicity/Carcinogenicity Study in Rats Exposedto Fluorocarbon 113 (FC-113). Trochimowicz, H. J., Rusch, G.M., Chiu, T., and Wood, C. K. (1988). Fundam Appl. Toxicol.11, 68–75. Groups of 100 male and 100 female CitCDBR ratswere exposed by whole-body inhalation to FC-113(1,1,2-trichloro-1,2,2-trifluoroethane)for 6 hr a day, 5 days a week for 24 months. Average exposureconcentrations (? 1 SD) were 0.0 (control), 2000 ? 100, 10,000? 500, and 20,000 ? 1000 ppm (v/v), respectively. Body weightswere consistently lower in both male and female rats in the20,000 ppm exposure group after approximately 1 and 4 months'exposure, respectively, and in female rats after 12 months'exposure at 10,000 ppm. Observations of appearance and behavior,mortality, and clinical laboratory measurements were unremarkableduring the 24-month exposure period. Despite exposure levelsas high as 20,000 ppm, only occasional slight increases in urinaryfluoride were seen. Microscopic examination of tissues fromrats examined during and at the end of the 24-month study revealedno evidence of compound-related toxicity or carcinogenicity.Based mainly on a 5 to 10% decrease in body weight gain at the10,000 and 20,000 ppm exposure levels, the no-observed-effectlevel for FC-113 in this study was 2000 ppm.     

Chronic Toxicity and Carcinogenicity Study of Erythritol in Rats

The potential toxicity and carcinogenicity of erythritol, a low-calorie sugar substitute, were examined in Wistar Crl:(WI) WU BR rats. Groups of 50 rats of each sex consumed diets with 0, 2, 5, or 10% erythritol, or 10% mannitol, for a period of 104–107 weeks. To each of these main groups, two satellite groups of 20 males each were attached for interim kills after 52 and 78 weeks of treatment. At start of the study, the rats were 5–6 weeks old. The average intakes of erythritol in the 2, 5, and 10% groups were 0.9, 2.2, and 4.6 g/kg body wt/day for males and 1.0, 2.6, and 5.4 g/kg body wt/day for females, respectively. Mannitol intakes were 4.4 and 5.2 g/kg body wt/day in males and females, respectively. All treatments were well tolerated without diarrhea or other side effects. Body weights were significantly below control levels during most of the study in males of the 5% erythritol group and in males and females of the 10% erythritol and 10% mannitol groups. Survival of the animals was not adversely affected by the treatments. Hematological and clinicochemical examinations did not reveal noticeable changes which could be attributed to treatment. Analysis of urine samples collected during five 48-hr periods, from rats of the satellite groups in Weeks 26, 42, 50, and 78 and from rats of the main groups in Week 102, showed that about 60% of ingested erythritol was excreted unchanged. The urine volumes increased with increasing dietary erythritol levels. In line with previous observations on other polyols, erythritol and mannitol ingestion led to an increased excretion of urinary calcium and citrate. The urinary excretions of sodium, potassium, phosphate,N-acetylglucosaminidase (NAG), γ-glutamyltransferase (GGT), low-molecular-weight protein (LMP), and total protein (TP) were slightly elevated in the 10% erythritol group. Increased GGT and NAG excretions also were seen occasionally at the 5% dose. Significantly increased relative cecum weights were seen in rats of either sex in the 10% mannitol and, somewhat less pronounced, 10% erythritol groups. Some cecal enlargement also was seen in the 5% erythritol group. The relative weight of the kidneys was highest in the 10% erythritol group, the difference from controls reaching statistical significance at interim kills (males) and termination (females). Except for more frequent pelvic nephrocalcinosis in female rats of all erythritol dose groups, the histopathological examinations did not reveal any nonneoplastic, preneoplastic, or neoplastic changes that could be attributed to the ingestion of erythritol. In male and female rats of the 10% mannitol group, pelvic nephrocalcinosis, which in females was associated occasionally with pelvic hyperplasia, was the only remarkable finding. The incidence and progression of nephrosis, which is commonly seen in aging rats of this strain, were not influenced by the treatments. In the absence of morphological alterations in the kidneys or other signs of nephrotoxicity, the increased excretions of NAG, GGT, LMP, and TP are regarded as innocuous, functional sequelae of the renal elimination of erythritol. In conclusion, the toxicological profile of erythritol in rats resembles that of other polyols in several respects. Except for nephrocalcinosis, which is commonly seen in polyol-fed rats, no other treatment-related, morphological changes were observed in the kidneys. Evidence for a tumor-inducing or tumor-promoting effect of erythritol was not seen.     

Preclinical Toxicology Studies with Acyclovir: Carcinogenicity Bioassays and Chronic Toxicity Tests

Preclinical Toxicology Studies with Acyclovir: CarcinogenicityBioassays and Chronic Toxicity Tests. Tucker, W.E., Jr., Krasny,H.C., de Miranda, P., Goldenthal, E.I., Elion, G.B., Hajian,G. and Szczech, G.M. (1983). Fundam. Appl. Toxicol. 3:579–586.Acyclovir (ACV), a nucleoside analog that is a new herpes-specificantiviral drug, was given by gavage at 50, 150 and 450 mg/kg/dayto Sprague Dawley rats and Swiss mice for most of their lifetimeto assess chronic toxicity and carcinogenicity. Treatment withACV did not shorten the lifespan of either rats or mice. Infact, female mice given 150 and 450 mg/kg/day had significantlylonger mean durations of survival than control female mice whenanalyzed by the life table technique. There were no signs oftoxicosis produced by chronic exposure to ACV in either therats or mice, and there was no drug-related increase in neoplasmsin either species. Four groups of Beagle dogs were initiallygiven daily oral doses of 15, 45 or 150 mg/kg ACV in a 1 yearchronic toxicity study. Dogs treated at 150 mg/ kg/day vomited,had diarrhea, consumed less feed and lost weight within 2 weeks.Dogs treated at 45 mg/kg/day also had minimal signs of gastrointestinaltoxicosis. These dose levels were then decreased to 60 and 30mg/kg/day for the rest of the one year test period. With theexception of occasional and inconsistent emesis and diarrhea,the 60 mg/kg/day dose level was well tolerated. Some mid andhigh dose dogs had sore paws due to erosion of footpads andcracking, splitting and loosening of the nails first becomingevident during the 13th week of the study. Several of thesedogs subsequently lost the keratin from some claws. There wasnail regeneration and healing of footpads as the study progressed,with all claws appearing essentially normal at the end of 1year. Nails and footpads of dogs given 15 mg/kg/day were normalthroughout the study.     

Subchronic and Chronic Inhalation Toxicity of Antimony Trioxide in the Rat

Fischer 344 rats were exposed by inhalation to Sb₂O₃ (antimonytrioxide) dust at exposure levels of 0, 0.25, 1.08, 4.92, and23.46 mg/m³ for 6 hr/day, 5 days/week for 13 weeks followedby a 27-week observation period. Subsequently, an inhalationon-cogenicity study was conducted at exposure levels of 0, 0.06,0.51, and 4.50 mg/m³ for 12 months followed by a 12-month observationperiod. The Sb₂O₃ in the subchronic study had a mass medianaerodynamic diameter (MMAD) of 3.05 ± 0.21 microns (mean± SD) with a geometric standard deviation (GSD) of 1.57± 0.06. In the chronic study, the MMAD was 3.76 ±0.84 and the GSD was 1.79 ± 0.32. Except for the eyes,no adverse clinical observations were attributed to Sb₂O₃ ineither study. In the subchronic study, corneal irregularitieswere seen after about 2 weeks of exposure and did not abateduring the observation period. In the chronic study, ophthalmoscopicevaluation at 24 months revealed a dose-related increase incataracts of 11, 24, 28, and 32% (both sexes combined) for eachgroup, respectively. Body weights were significantly lower (6%)than the control group's weights in the 23.46 mg/m³ males inthe subchronic study. These rats did not recover this weightduring the 27-week observation period. Body weights of the femalesin both studies and males in the chronic study were unaffected.There were no Sb₂O₃ effects on clinical chemistry or he-matologyin either study. Mean absolute and relative lung weights weresignificantly increased in the 4.92 and 23.46 mg/m³ groups inthe subchronic study. The 23.46 mg/m³ group's lung weights didnot recover to control levels during the 27-week observationperiod. Lung weights for rats in the chronic study were unaffected.Microscopic changes in the lungs in the subchronic and chronicstudy were limited to subacute-chronic interstitial inflammation,increased numbers of alveolar-in-traalveolar macrophages, foreignmaterial in the alveolar-in-traalveolar macrophages in the peribronchialand perivascular (chronic study only) lymphoid aggregates andin the peribronchial lymph nodes, granulomatous inflammation/granulomas,and fibrosis. In the chronic study, any observed neoplasms occurredwith comparable incidence among all groups and were within thehistorical range for controls. Clearance of Sb₂O₃ from the lungwas burden dependent and was reduced by 80/ in the 4.50 mg/m³group in the chronic study. The previously reported studies,which found Sb₂O₃ to be a carcinogen, were run at higher lungburdens. Under the exposure conditions of the current study,Sb₂O₃ was not a carcinogen.     

Toxicity and Carcinogenicity of Chronic Exposure to Tris(2-chloroethyl)phosphate

Previous short-term studies of tris(2-chloroethyl)phosphate(TRCP), a flame retardant used in industrial and consumer products,demonstrated that repeated administration of 350 mg TRCP/kgbody wt by oral gavage resulted in necrosis of pyramidal neuronsin the CA1 region of the hippocampus of F344 rats, but not inB6C3F₁ mice. The 2-year studies reported here were designedto characterize the chronic toxicity and potential carcinogenicityof TRCP in each sex of F344 rats and B6C3F₁ mice. Groups of60 rats per sex received 0, 44, or 88 mg/kg by oral gavage,once per day, 5 days per week, for up to 103 weeks. Groups of60 mice per sex received 0, 175, or 350 mg/kg by oral gavageon the same dosing schedule. Each of these groups contained10 animals which were euthanized at 66 weeks. The principaltoxic effects of chronic exposure of rats to TRCP occurred inthe brain and kidney. In contrast to the findings in the 16-weekstudies, a hippocampal lesion was not observed in the brain,although degenerative lesions were widely distributed in thegray and white matter of the brain stem and cerebral cortexof high-dose female and, to a lesser extent, male rats. Thesefindings suggest that the hippocampal necrosis may be dependentupon the size of the individual doses or may have a pathogenesisdifferent from that of the lesions in the brain stem and cerebralcortex. The other primary effect of chronic exposure was a dose-dependentincreased incidence of renal tubule hyperplasia and adenoma.Renal tubule neoplasms, primarily adenomas, were observed in4% of control, 10% of low-dose, and 50% of high-dose male ratsand in 0% of control, 4% of low-dose, and 10% of high-dose femalerats. There were also marginal increases in mononuclear cellleukemia and in thyroid follicular neoplasms in dosed male andfemale rats that were not clearly related to TRCP administration.Mice were less sensitive to TRCP than rats and lesions attributableto chemical administration in mice were limited to a dose-dependentincreased incidence of karyomegaly (nuclear enlargement) inepithelial cells of proximal tubules in the inner cortex andouter stripe of the outer medulla of the kidneys both sexes.Marginal increases in the incidence of renal tubule neoplasmsin male mice and harderian gland neoplasms in female mice werenot considered clearly related to TRCP administration.     

Mechanisms of Chromium Carcinogenicity and Toxicity

Abstract

Chromium, like many transition metal elements, is essential to life at low concentrations yet toxic to many systems at higher concentrations. In addition to the overt symptoms of acute chromium toxicity, delayed manifestations of chromium exposure become apparent by subsequent increases in the incidence of various human cancers. Chromium is widely used in numerous industrial processes, and as a result is a contaminant of many environmental systems. Chromium, in its myriad chemical forms and oxidation states, has been well studied in terms of its general chemistry and its interactions with biological molecules. However, the precise mechanisms by which chromium is both an essential metal and a carcinogen are not yet fully clear. The following review does not seek to embellish upon the proposed mechanisms of the toxic and carcinogenic actions of chromium, but rather provides a comprehensive review of these theories. The chemical nature of chromium compounds and how these properties impact upon the interactions of chromium with cellular and genetic targets, including animal and human hosts, are discussed.     

Chronic Toxicity and Carcinogenicity Studies with the {beta}-Adrenoceptor Antagonist Levobunolol

The chronic toxicity and carcinogenicity of levobunolol, a nonselectiveß-adrenoceptor antagonist, was evaluated in Swissmice and Wistar rats. The drug was administered in the dietto mice at 0, 12, 50, and 200 mg/kg/day for 80 weeks and torats at 0, 0.5, 2, 5, 30, and 180 mg/kg/day for 2 years. Inmice, uterine leiomyomas were present in 4 of 50 females at200 mg/kg but not in any other group. The incidences of othertumor types, as well as pathologic findings, were comparableamong groups. In rats, significant body weight gain suppressionoccurred at 5, 30, and 180 mg/kg. Brown discoloration of perianalfur and steel-gray discoloration of hairless skin were evidentin high-dose rats. A generalized steel-gray discoloration ofinternal organs and tissues occurred in the 30 and 180 mg/kggroups. No other differences between treated and control groupswere evident. The clinical relevance of the increased incidenceof uterine leiomyoma in mice is questionable because it occurredonly in one species at more than 200 times the projected therapeuticdose.     

Chronic Inhalation Toxicity of Size-Separated Glass Fibers in Fischer 344 Rats

This study was initiated to determine the chronic biologicaleffects in Fisher 344 rats of inhaled size-separated respirablefractions of fibrous glass (FG) having compositions representativeof common building insulation wools. Rats were exposed usingnose-only inhalation chambers, 6 hr/day, 5 days/week, for 24months to three concentrations (3, 16, and 30 mg/m³) of twodifferent compositions of FG (designated MMVF 10 and MMVF 11),or to filtered air (negative control). Fibrous glass findingswere compared to those from a concurrent inhalation study ofchrysotile asbestos and refractory ceramic fiber (RCF). TheFGs used in this study were size selected to be largely respirablein the rat and the aerosol generation technique did not alterthe dimensions of the fibers. Interim euthanizations took placeat 3- to 6-month intervals to monitor progression of pulmonarychanges. Fibers were recovered from digested lung tissue fordetermination of changes in fiber number and morphology. Inanimals exposed to 30 mg/m³ of MMVF 10 or MMVF 11, 4.2±0.9x10⁵and 6.4±3.1x10⁵ fibers/mg dry lung tissue, respectively,were recovered after 24 months of exposure. Exposure to chrysotileasbestos (10 mg/m³) and to a lesser extent RCF (30 mg/m³) resultedin pulmonary fibrosis as well as mesothelioma and significantincreases in lung tumors. FG exposure was associated with anonspecific inflammatory response (macrophage response) in thelungs that did not appear to progress after 6–12 monthsof exposure. These cellular changes are reversible and are similarto the effects observed after inhalation of an inert dust. Nolung fibrosis was observed in the FG-exposed animals. Further,FG exposure resulted in no mesotheliomas and no statisticallysignificant increase in lung tumor incidence when compared tothat of the negative control group. These findings, along withprevious inhalation studies, suggest that respirable fibrousglass does not represent a significant hazard for fibrotic orneoplastic lung disease in humans.     

Chronic Toxicity and Carcinogenicity of Methylmercury Chloride in B6C3F1 Mice

Chronic Toxicity and Carcinogenicity of Methylmercury Chloridein B6C3F1 Mice. MRRSU-MORI, K., HIRANO, M., UEDA, H., MAITA,K., AND SHIRASU, Y. (1990). Fundam. Appl. Toxicol. 14, 179–190.A 2-year feeding study of methylmercury chloride (MMC: 0, 0.4,2, or 10 ppm) was conducted in B6C3F1 mice (60 mice of eachsex/group) to compare chronic toxicity and carcinogenicity resultswith those for ICR mice from our previous study in which malesof the 10-ppm group showed an increased incidence of renal tumorswithout any abnormal in-life parameters. In B6C3F1 mice of the10-ppm group, neurotoxic signs characterized by posterior paralysiswere observed in 33 males after 59 weeks and in 3 females after80 weeks. In males, a marked increase in mortality and a remarkabledecrease in body weight gain were observed after 60 weeks. Toxicencephalopathy consisting of neuronal necrosis of the brainand toxic peripheral sensory neuropathy were induced in bothsexes in this group. Chronic nephropathy, testicular atrophy,and glandular stomach ulcer increased in incidence in the males;chronic nephropathy also increased in incidence in females.In proliferative lesions, there were significant increases inthe incidence of renal adenoma and/or carcinoma (16/60) andtubular cell hyperplasia (14/ 60) in males of the 10-ppm group,as compared to the control group. The incidence of chronic nephropathyalso increased in males of the 2-ppm group. The results of thisstudy indicate that the susceptibility of B6C3F1 mice to renaltoxicity and renal carcinogenicity is comparable to that ofICR mice, and B6C3F1 mice are more sensitive to the chronicneurotoxic effects of MMC than are ICR mice.     

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 Carcinogenicity Studies of Triethanolamine in B6C3F1 Mice

The chronic toxicity and carcinogenic potential of triethanolaminewas examined in B6C3F1 mice. Triethanolamine, dissolved in distilledwater at levels of 0 (control), 1, and 2%, was given to groupsof 50 males and 50 females ad libitum in drinking water for82 weeks. Neoplasms developed in all groups, including the controlgroup, but no dose-related increase of the incidence of anytumor was observed in treated groups of both sexes. There wereno adverse effects as regards survival of the mice, organ weights,and specific incidence of neoplasms in the treated, comparedto the control group. This chronic toxicity test provides noevidence of carcinogenic potential of triethanolamine in B6C3F1mice.     

Chronic Toxicity and Carcinogenicity Studies of 2-Methylnaphthalene in B6C3F1 Mice

The toxicity and carcinogenic potential of 2-methylnaphthalene(2-MN) were examined in B6C3F₁ mice. Groups of 50 male and 50female mice were given diets containing 0, 0.075, and 0.15%2-MN for 81 weeks. Both 0.075 and 0.15% 2-MN caused pulmonaryalveolar proteinosis at high incidence: 55.1 and 45.8% in femalesand 42.9 and 46.9% in males, respectively. The incidences oftotal lung tumors, including bronchiolar/alveolar adenomas andcarcinomas, were 20.4 and 12.2% in male mice given 0.075 and0.15% 2-MN, respectively, the former value being significantlyincreased compared with the 4.1% in control males. However,in the respective incidences of the adenomas and carcinomas,neither in-tergroup differences nor dose dependencies were observed.The incidences of other tumors did not differ between mice treatedwith 2-MN and the controls. The results indicated that 2-MNinduces pulmonary alveolar proteinosis but does not possessunequivocal carcinogenic potential in B6C3F₁ mice.     

Chronic Toxicity and Carcinogenicity Studies of 1-Methylnaphthalene in B6C3F1 Mice

The carcinogenic potential of 1-methylnaphthalene (1-MN), acompound which exists widely in the environment, was investigatedin B6C3F1 mice. Groups of 50 male and 50 female mice were givendiets containing 0, 0.075, or 0.15% 1-MN for 81 weeks. Bothtreatment groups developed pulmonary alveolar proteinosis athigh incidence, with 46.0 and 34.7% of females and 46.0 and38.0% of males, respectively, being affected. Total lipid andphospholipid levels in sera and monocytes in peripheral bloodwere also significantly increased in 1-MN-treated female andmale mice in contrast with control values. The incidences ofbronchiolar/alveolar adenomas in the lungs of male mice givenboth 0.075 or 0.15% 1-MN were 26.0 and 24.0%, respectively,in both cases significantly increased in contrast with the 4.1%observed for control males. However, neither dose dependencenor significant difference in the incidences of bronchiolar/alveolarcarcinomas between 1-MN-treated and control male mice was observed.The incidences of other tumors also were similar in both 1-MN-treatedand control groups. The results of the present experiment thussuggested a possible weak carcinogenic potential of 1-MN tothe lung of male but not female B6C3F1 mice.     

Toxicity and Carcinogenicity of Chromium Compounds in Humans

Chromium is a human carcinogen primarily by inhalation exposure in occupational settings. Although lung cancer has been established as a consequence of hexavalent chromium exposure in smokers and nonsmokers, some cancers of other tissues of the gastrointestinal and central nervous systems have also been noted. Except for a few reports from China, little is known about the health risks of environmental exposures to chromium. Likewise, there has been a lack of epidemiological studies of human exposure to hexavalent Cr by drinking water or ingestion, and it has been suggested that humans can perhaps tolerate hexavalent Cr at higher levels than the current drinking water standard of 50 ppb. This review highlights the most recent data on the induction of skin tumors in mice by chronic drinking-water exposure to hexavalent chromium in combination with solar ultraviolet light. This experimental system represents an important new animal model for chromate-induced cancers by ingestion of drinking water, and it suggests by extrapolation that chromate can likely be considered a human carcinogen by ingestion as well. The potential use of this animal model for future risk assessment is discussed.