Inhalation carcinogenicity of epichlorohydrin in noninbred Sprague-Dawley rats.

Inhalation exposure experiments with the direct-acting alkylating agent epichlorohydrin (ECH) were done on noninbred male Sprague-Dawley rats. Single 6-hour exposure to ECH and follow-up for 14 days showed the median lethal concentration to be about 360 ppm. Further inhalation experiments were done with 6-hour exposure 5 days/week. A short-term 30-exposure regimen with 100 ppm ECH produced malignant squamous cell carcinomas of the nasal cavity in 15 of 140 rats and respiratory tract papillomas in 3 rats. Among 100 rats, lifetime exposure to 30 ppm yielded 1 malignant squamous carcinoma of the nasal cavity plus 1 nasal papilloma. No nasal or respiratory tract tumors were produced by lifetime exposure of 100 rats to 10 ppm. As controls, 100 air-treated and 50 untreated rats were used. A dose-rate effect was observed for ECH inasmuch as 30-day exposure to 100 ppm (3,000 ppm-days) produced 15 cancers in comparison to the 1 cancer from the lifetime exposure to 30 ppm (8,700 ppm-days) and no cancers from lifetime exposure to 10 ppm (2,500 ppm-days).

Structure and tumor-promoting activity of analogues of anthralin (1,8-dihydroxy-9-anthrone).

Seventeen analogues of the tumor-promoting agent anthralin were tested for the same biological property by repeated skin application on mouse skin using female ICR/Ha Swiss mice, after a single application of a subcarcinogenic dose of 7,12-dimethylbenz[a]anthracene. Seven of the compounds tested are new compounds. They are 1,8-diacetoxy-9-anthrone, 1,8-dimyristoyloxy-9-anthrone, 1,8-dihydroxy-10-acetyl-9-anthrone, 1,8-dihydroxy-10-myristoyl-9-anthrone, 1,8,10-trihydroxy-9-anthrone, 1,8-dihydroxy-9,10-dihydroanthracene, and myristoyljuglone. All compounds were used in pure form for the bioassays. Of the 17 test compounds four showed notable tumor-promoting activity. They are 1,8-dihydroxy-10-acetyl-9-anthrone, 1,8-dihydroxy-10-myristoyl-9-anthrone, 1-hydroxy-9-anthrone, and juglone. In order to determine whether there is any relationship between tumor-promoting activity and metal chelation in this series, the chelating abilities of anthralin and of its inactive analogue 1,8-dihydroxyanthraquinone were examined using the bivalent metal ions Cu(II), Zn(II), Mn(II), Mg(II), and Ca(II). No relationship between chelation and tumor-promoting ability was found.

The acute, genetic, developmental, and inhalation toxicology of 1,1,1,3,3-pentafluoropropane (HFC 245fa).

1,1,1,3,3-Pentafluoropropane (HFC 245fa) is a volatile, low boiling liquid. It was inactive in a reverse mutation (Ames) assay using five strains of Salmonella typhimurium and one strain of Escherichia coli. It was also inactive in an in vivo mouse micronucleus assay with exposures of 101,000 ppm. In a chromosome aberration study with human lymphocytes, some activity was seen when cell cultures were exposed to atmospheres of 30% v/v or higher for 24 h without metabolic activation. No activity was seen in assays using less than 30% v/v or exposure times of less than 24 h. No activity was seen in the presence of metabolic activation even with exposures of 70%. It was not toxic by the dermal route. There was no mortality or significant signs of toxicity when rats and mice were given 4- h exposures to levels of 203,000 ppm or 101,000 ppm of HFC 245fa, respectively. In a cardiac sensitization study with dogs involving intravenous administration of epinephrine, the no observed effect level (NOEL) was 34,000 ppm and the threshold for a response was 44,000 ppm. In a rat inhalation, developmental toxicity study, a slight reduction in pup weight was seen at 50,000 ppm, but not at 10,000 ppm. There were no developmental effects at any level. A series of three inhalation toxicity studies were conducted. All involved daily 6-h exposures up to 50,000 ppm. The first study involved 14 consecutive snout-only exposures. There were no treatment-related effects on body weight, survival, or histologic parameters. BUN, GPT, and GOT levels frequently were elevated compared to controls , whereas cholesterol levels tended to be lower. The second study involved 28 consecutive whole-body exposures. Again, there were no treatment related effects on body weight, survival, or histological parameters. Urine volume was increased. Increases were also seen in several red blood cell parameters. These may be related to partial dehydration. Increases were seen in BUN levels and alkaline phosphatase (AP), GPT, GOT and CPK activities, primarily in rats exposed at 10,000 and 50,000 ppm. Urinary fluoride levels were also elevated in an exposure- related pattern. In the third study, whole-body exposures were conducted 5 days per week for 13 weeks. There were no treatment-related effects on survival, clinical observations, body weight gain, or food consumption. Urine volumes were increased, urinary fluoride levels were elevated, and increases were seen in red blood cell counts, and related parameters and increases were seen in AP, GOT, GPT and CPK activities. These effects were seen in the 10,000 and 50,000 ppm exposure level groups. Histopathologic examination did not show any effects on the kidney, liver, or lungs. There was an increased incidence of myocarditis in all animals exposed at 50,000 ppm and the majority exposed at 10,000 ppm. It was described as mild. Based on these findings, 2000 ppm appears to be a no observed adverse effect level.

Subchronic inhalation toxicity study of caprolactam (with a 4-week recovery) in the rat via whole-body exposures.

This study was designed to assess the potential subchronic inhalation toxicity of caprolactam when administered as a 3-micron aerosol from an aqueous solution to Sprague-Dawley CD rats (10/sex/group) via whole-body exposure. The study was enhanced with the inclusion of motor activity measurements and a functional observational battery to assess the neurotoxic potential of caprolactam. The rats were exposed at least 65 times over a 13-week period for 6 h per day, 5 days per week, to target concentrations (3 microns, mass median aerodynamic diameter) of 0, 25, 75, and 250 milligrams per cubic meter (mg/m3). An additional 10 animals/sex/group were similarly exposed and then held for a 4-week recovery period. Exposure levels were determined gravimetrically six times daily; one daily sample was analyzed by high-pressure liquid chromatography. No deaths were observed in the study during the exposure or recovery periods. Treatment-related responses such as labored breathing and nasal discharge were seen during many of the exposures. Similar responses as well as moist rales were seen during the nonexposure periods during the 13 weeks of exposure. However, these responses abated during the 4-week recovery period. There were no clearly treatment-related responses observed with ophthalmoscopic examinations, body weight measurements, food consumption measurements, neurobehavioral evaluations, clinical pathology evaluations, organ weight measurements, or macroscopic pathology examinations. Microscopic findings that were considered related to exposure to the test material were seen in the nasoturbinal tissues (hypertrophy/hyperplasia of goblet cells in the respiratory mucosa and intracytoplasmic eosinophilic material in epithelial cells of the olfactory mucosa) of the two higher-exposure group animals and in the laryngeal tissues (squamous/squamoid metaplasia/hyperplasia of the pseudostratified columnar epithelium covering the ventral seromucous gland) of all three exposure group animals. These changes were considered to be adaptive responses to an irritant (caprolactam). The keratinization of the metaplastic epithelium in the larynx was considered to be an adverse effect. By the end of the 4-week recovery period, there was complete regression of the keratinization in the larynx, but recovery of the adaptive nasoturbinal effects had not completely resolved. In conclusion, the whole-body exposure of Sprague-Dawley rats to caprolactam as a respirable aerosol for 6 h/day, 5 days/week, for 13 weeks at gravimetrically determined levels of 24, 70, and 243 mg/m3 resulted in respiratory tract effects (laryngeal) at the highest exposure level with complete recovery within 4 weeks postexposure. The results indicate that the no-observed-adverse-effect level for caprolactam is 70 mg/m3, based on upper respiratory effects, with 243 mg/m3 representing a no-observed-effect level for systemic toxicity, neurotoxicity, and lower respiratory tract effects.

Four-week repeated inhalation study of HCFC 225ca and HCFC 225cb in the common marmoset.

Four male and three female marmosets in each group were exposed to air only, 1000 ppm of HCFC 225ca or 5000 ppm of HCFC 225cb, for 6 h per day for 28 consecutive days. HCFC 225ca caused a slight reduction in body weight. HCFC 225cb occasionally caused somnolence during exposure and vomiting on the first day of exposure. Clinical chemistry findings included a mild reduction of triglyceride, cholesterol and phospholipid levels and increased GOT level in the HCFC 225ca exposure group. HCFC 225cb also caused a reduction of triglyceride levels in some animals. HCFC 225ca caused a slight increase of hepatic carnitine palmitoyltransferase (CPT) activity while HCFC 225cb slightly increased cyanide-insensitive palmitoyl CoA beta-oxidation (FAOS) activity. In the HCFC 225cb exposure group, an increase in cytochrome P-450 content was also observed. HCFC 225ca caused a fatty change in the hepatic cells. Increased incidence of lipid droplets in the hepatic cells and myelin-like bodies in hepatic cells, Kupffer's cells and hepatic blood vessels were observed electron microscopically in the HCFC 225ca exposure group. A proliferation of smooth endoplasmic reticulum was observed in the HCFC 225cb exposure group. Decreased peroxisome volume density in the HCFC 225ca group, and increased volume density in the HCFC 225cb exposed females were seen. However, organ weight measurement and histopathological examination did not reveal hepatomegaly or hypertrophy with either substance. Although slight changes were noticed in peroxisome volume density and in some of the peroxisomal enzyme activities, the changes related to peroxisome proliferation with HCFC 225ca and 225cb were minimal in marmosets compared to those seen in rats. Histopathological examination and hormonal analysis did not reveal any abnormalities in the pancreas or testes.

Topical treatments for hydrofluoric acid dermal burns. Further assessment of efficacy using an experimental piq model.

Several topical treatments for hydrofluoric acid dermal burns (Zephiran, calcium acetate and magnesium hydroxide antacid soaks, and calcium gluconate gel) were assessed for efficacy in a pig model. Gross appearance and histopathology of treated and untreated burn sites were evaluated. For superficial burns, Zephiran was most effective; calcium acetate, magnesium hydroxide antacid, and calcium gluconate gel were less effective. For deep burns, gross observations showed that calcium acetate and Zephiran were most efficacious, whereas histopathology indicated comparable efficacy of Zephiran, calcium acetate, and calcium gluconate gel for all skin layers. Magnesium hydroxide antacid demonstrated efficacy only for the subdermis. The clinically beneficial effects of both Zephiran and calcium gluconate gel were affirmed. Although results suggest that calcium acetate and magnesium-containing antacids may be beneficial for human hydrofluoric acid dermal burns, these are not established clinical treatments.

Inhalation teratology and two-generation reproduction studies with 1,1-dichloro-1-fluoroethane (HCFC-141b).

HCFC-141b is one of the chemicals being considered as a replacement for CFC 11 in solvent and foam-blowing applications. Teratology studies were conducted in both rats and rabbits and a two-generation reproduction inhalation toxicity study was conducted in rats. The pregnant rabbits were exposed to levels of 0 (control), 1400, 4200 and 12,600 ppm HCFC-141b from day 7 to day 19 of gestation (6 hr/day). There was no evidence of developmental or teratogenic effects on the foetuses. The pregnant rats in the teratology study were exposed to levels of 0 (control), 3200, 8000 and 20,000 ppm from days 6 to 15 of gestation (6 hr/day). In the 20,000 ppm exposure group, there was an increase in implantation losses; furthermore, in this group, foetal weights tended to be lower than controls. As with the rabbits, there was no evidence of a teratogenic effect. The reproduction study was conducted at exposure levels of 0, 2000, 8000 and 20,000 ppm, 7 days/wk starting approximately 10 wk before the first pairing. Adult rats exposed at 20,000 ppm (and, to a lesser extent, those exposed to 8000 ppm) showed increases in water intake, slight increases in food consumption, and decreases in body weight. Following the mating of the F0 parents, there were fewer litters in the 20,000 ppm exposure level group than in controls. When these parents were then paired with different partners, again, the number of litters was lower in the 20,000 ppm group, although most of the animals that did not produce litters the first time mated successfully the second time. When the F1 animals were mated to produce the second generation, the number of litters was comparable for all groups. In the second F0 mating and the F1 mating, the number of pups per litter was lower at 20,000 ppm; although birth weights were comparable, body weight gain tended to be slower in the high-level exposure group. Survival was good in all groups. At 8000 ppm no significant effects were observed in the pups and only minimal signs in the adults. The 2000 ppm exposure level represented a clear no-observed-effect level for all indices.

Acute and subchronic toxicity of 1,1-dichloro-1-fluoroethane (HCFC-141b).

The acute and subchronic toxicity of 1,1-dichloro-1-fluoroethane (HCFC-141b), a CFC alternative, was evaluated in several acute and subchronic studies to assist in establishing proper handling guides. Data from acute toxicity studies in rats and rabbits demonstrated that HCFC-141b has very low acute toxicity. HCFC-141b was not a skin irritant, but was a mild eye irritant, in rabbits and was not a skin sensitizer in guinea pigs. Skin application of HCFC-141b to rabbits at 2000 mg/kg body weight produced no adverse effects. Oral administration at 5000 mg/kg body weight did not cause any deaths or clinical signs of toxicity in rats. The 4-hr LC50 for HCFC-141b was about 62,000 ppm in rats. Repeated exposures of rats for 6 hr/day, 5 days/wk for up to 90 days at concentrations of 2000, 8000 or 20,000 ppm did not result in significant adverse effects. Minor, but dose-dependent, reductions in body weight were observed in male and female rats during the 90-day study. Decreased responsiveness was also observed in rats but only at 20,000 ppm. An increase in serum cholesterol or triglycerides was observed in male and female rats at 20,000 ppm, and in males at 8000 ppm. No specific organ pathology was noted in these subchronic inhalation studies. The no-observable-adverse-effect level (NOAEL) from these studies was 8000 ppm. Results from other studies demonstrate that HCFC-141b was not neurotoxic in rats. As with trichlorofluoroethane (CFC-11), a cardiac sensitization response to an intravenous epinephrine challenge occurred in dogs with HCFC-141b at 5000 ppm and higher concentrations in experimental screening studies.

Unexpected brain lesions in lactating Sprague-Dawley rats in a Two-generation Inhalation Reproductive Toxicity Study with pentafluoropropane (HFC-245fa).

The study presented was conducted following the reproductive study guideline OECD Guideline 416 Two-Generation Reproduction Toxicity Study. Sprague-Dawley rats were exposed to 2000, 10,000 and 50,000 ppm of HFC-245fa. There was an unexpected mortality of lactating dams in the medium and high dose group beginning at day 10 of lactation. Statistically significant histopathological alterations were observed in the cerebellum of a total of 9/30 females of the high dose group of the F0-generation and in 10/27 females of the high dose group of the F1-generation. In contrast there were no brain lesions found in males or non-pregnant females of all dose groups. Neuronal necrosis and degeneration in the cerebellar cortex were observed as the most severe finding. Furthermore vacuolation of the neuropil in different degrees was diagnosed in 7/30 females of the F0-generation and in 9/30 females of the F1-generation. Acute hemorrhages - in particular perivascular - occurred in 5/30 females of the F0- and in 5/30 females of the F1-generation indicating a disturbed vascular integrity. The main lesions found in the cerebrum were glial scars in the corpus callosum and restricted to 2/30 females of the F0-generation of the high dose group. The increased incidence of myocardial fibrosis and mononuclear cell infiltration in males - indicating myocarditis - was only seen in the F0-generation of the high dose group. Females of the F1-generation of the high dose group showed an increased incidence of minimal myocardial fibrosis. In summary, histopathology revealed that the brain, particularly the cerebellum, and to a minor degree the heart turned out to be the toxicological target organs of the substance. Presumably substance-related energy deprivation may be responsible for the observed changes. One of the metabolites, 3,3,3-trifluoropropanoic acid has been shown to be capable of causing this effect.

Environmental service payments: evaluating biodiversity conservation trade-offs and cost-efficiency in the Osa Conservation Area, Costa Rica.

The cost-efficiency of payments for environmental services (PES) to private landowners in the Osa Conservation Area, Costa Rica, is evaluated in terms of the trade-off between biodiversity representation and opportunity costs of conservation to agricultural and forestry land-use. Using available GIS data and an 'off-the-shelf' software application called TARGET, we find that the PES allocation criteria applied by authorities in 2002-2003 were more than twice as cost-efficient as criteria applied during 1999-2001. Results show that a policy relevant assessment of the cost-effectiveness of PES relative to other conservation policies can be carried out at regional level using available studies and GIS data. However, there are a number of data and conceptual limitations to using heuristic optimisation algorithms in the analysis of the cost-efficiency of PES. Site specific data on probabilities of land-use change, and a detailed specification of opportunity costs of farm land, labour and capital are required to use algorithms such as TARGET for ranking individual sites based on cost-efficiency. Despite its conceptual soundness for regional conservation analysis, biodiversity complementarity presents a practical challenge as a criterion for PES eligibility at farm level because it varies depending on the set of areas under PES contracts at any one time.

The measuring and monitoring of formaldehyde in inhalation test atmospheres.

The formaldehyde levels in the exposure chambers used for a six-month inhalation study were measured by collecting impinger samples which were analyzed by the chromotropic acid colorimetric method. The levels were also monitored continuously by CEA 555 air monitors. In developing a joint laboratory analytical program, one version of the chromotropic acid procedure was found to give erroneous results. Difficulties were also experienced due to sample contamination during shipment. It was shown that dilute formaldehyde solutions in 1% sodium bisulfite were much more stable than aqueous solutions. Adoption of satisfactory sample shipment methods and standarization of the analytical procedure produced good agreement in the results obtained for impinger samples analyzed by both laboratories.

A 26-week inhalation toxicity study with formaldehyde in the monkey, rat, and hamster.

This inhalation study involved simultaneous exposure of five groups of 6 male Cynomolgus monkeys, 20 male and 20 female Fischer 344 rats, and 10 male and 10 female Syrian golden hamsters for 22 hr per day, 7 days per week for 26 weeks to formaldehyde gas. The cumulative mean exposure concentrations were 0, 0, 0.19, 0.98, and 2.95 ppm for the two control groups, low-, mid-, and high-level exposure groups, respectively. There was no treatment-related mortality during the study. In monkeys, the most significant findings were hoarseness and congestion and squamous cell metaplasia in the nasal turbinates of the 2.95-ppm exposure group. There were no signs of toxicity in the lower-level exposure groups. In the rat, the only observations of possible responses to exposure were found in the 2.95-ppm exposure group. These findings consisted of squamous metaplasia in the nasal turbinates, decreased body weights starting during the second week of the study, and decreased liver weights. In contrast to monkeys and rats, hamsters did not show any significant responses to exposure even at 2.95 ppm. It was concluded that nearly continuous exposure of monkeys and rats for six months at a level of 2.95 ppm of formaldehyde clearly elicited an effect while exposures below this level did not appear to demonstrate an effect. It further appeared that the monkey and rat were more sensitive to formaldehyde exposure than the hamster.

Variability of a mouse ear swelling test (MEST) in predicting weak and moderate contact sensitization.

An investigation was conducted at two independent laboratories for the purpose of evaluating the ability of a mouse ear swelling test (MEST), previously developed and validated by S.C. Gad. B.J. Dunn, D. W. Dobbs, C. Reilly, and R.D. Walsh (1986, Toxicol. Appl. Pharmacol. 84, 93-114), to predict contact sensitization induced by weak to moderate contact sensitizers. Twenty-six coded chemicals, 23 with weak to strong potential to induce sensitization in animals and/or humans and 3 negative controls, were investigated. Each laboratory tested 18 materials: 10 chemicals were common to both labs and 16 chemicals were divided so that 8 were unique to each of the two labs. The methods and chemicals utilized were the same as those used and reported by Gad et al. (1986) and, therefore, data generated from this investigation were compared to results from their research. Contrary to results reported by Gad and co-workers, findings from the present study suggest that this MEST is a useful model for identifying strong contact sensitizers, but is not reliable for detecting weak to moderate allergens.

Chronic inhalation toxicity/carcinogenicity study in rats exposed to fluorocarbon 113 (FC-113).

Groups of 100 male and 100 female Crl:CDBR rats were 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 exposure concentrations (+/- 1 SD) were 0.0 (control), 2000 +/- 100, 10,000 +/- 500, and 20,000 +/- 1000 ppm (v/v), respectively. Body weights were consistently lower in both male and female rats in the 20,000 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 unremarkable during the 24-month exposure period. Despite exposure levels as high as 20,000 ppm, only occasional slight increases in urinary fluoride were seen. Microscopic examination of tissues from rats examined during and at the end of the 24-month study revealed no evidence of compound-related toxicity or carcinogenicity. Based mainly on a 5 to 10% decrease in body weight gain at the 10,000 and 20,000 ppm exposure levels, the no-observed-effect level for FC-113 in this study was 2000 ppm.

Metabolism of 1,1-dichloro-1-fluoroethane (HCFC-141b) in human volunteers.

Human subjects were exposed by inhalation to 250, 500, and 1000 ppm 1,1-dichloro-1-fluoroethane (HCFC-141b) for 4 hr, and urine samples were collected from 0-4, 4-12, and 12-24 hr for metabolite analysis. 19F nuclear magnetic resonance spectroscopic analysis of urine samples from exposed subjects showed that 2,2-dichloro-2-fluoroethyl glucuronide and dichlorofluoroacetic acid were the major and minor metabolites, respectively, of HCFC-141b. Urinary 2, 2-dichloro-2-fluoroethyl glucuronide was hydrolyzed to 2, 2-dichloro-2-fluoroethanol by incubation with beta-glucuronidase, and the released 2,2-dichloro-2-fluoroethanol was quantified by gas chromatography/mass spectrometry. Concentrations of 2, 2-dichloro-2-fluoroethanol were highest in the urine samples collected 4-12 hr after exposure, but 2,2-dichloro-2-fluoroethanol was also detected in the samples collected 0-4 and 12-24 hr after exposure. Exposure concentration-dependent excretion of 2, 2-dichloro-2-fluoroethanol, obtained by hydrolysis of 2, 2-dichloro-2-fluoroethyl glucuronide, was observed in seven of the eight subjects studied. In conclusion, HCFC-141b is metabolized in human subjects to 2,2-dichloro-2-fluoroethanol, which is conjugated with glucuronic acid and excreted as its glucuronide in urine in a time- and exposure concentration-dependent manner.

Subchronic inhalation toxicity and reproductive assessment in rats of three chlorinated propenes.

Groups of 15 male and 15 female Sprague-Dawley rats were exposed to 1 of 3 chloropropene (2,3-Di = DCP; 1,2,3-Tri = TRCP; and 1,1,2,3-Tetra = TECP) vapors to provide information on repeated exposures and the potential for reproductive impairment by the most likely route of occupational exposure. Target exposure concentrations were 0, 1, 5, and 15 ppm, 6 h/d, 5 d/wk for 13 wk. The following parameters were evaluated: pharmacotoxic signs, survival, body weights, hematology, clinical blood chemistry, urine analysis, gross and histopathology (over 40 tissues/rat), organ weights, and selected weight ratios. Signs of nasal irritation were noted in rats exposed to 15 ppm of either DCP or TRCP but not TECP. Small decreases in overall body weight were observed in female rats exposed to 15 ppm TCP. An increase (approximately 15%) in spleen weight, with no corresponding histopathological or clinical findings, was observed in 15 ppm DCP-treated male rats. No other effects considered related to treatment were observed following exposure to any of the three chlorinated propenes. Additional groups of 10 male and 20 female Sprague-Dawley rats were exposed to DCP, TRCP, or TECP vapors at target concentrations of 0, 1, or 5 ppm for 6 h/d, 5 d/wk for a 10-wk premating period, a mating period, and the first 14 d (females only) of gestation. Females were allowed to deliver litters and the offspring were evaluated during a 21-d lactation period. Mating, pregnancy, and fertility indices were generally comparable among all test groups, although female mating and pregnancy indices of both DCP-treated females were lower than expected in the regular and postrecovery reproduction phase. No effects were seen on pup survival, sex distribution, body weights, organ weights, and ratios. A modest reduction in pup body weights was observed following TECP exposure but was attributed to large litter size. No treatment-related effects were seen following necropsy of adults or weanlings, nor were such effects noted following microscopic evaluation of gonads from parental animals.

Acute inhalation study in the rat of comparative uptake, distribution and excretion for different cadmium containing materials.

Single 2-hr inhalation exposures were conducted at levels of approximately 100 mg/m3 (based on cadmium content) with the use of two cadmium pigments (cadmium red and cadmium yellow), a dust of cadmium carbonate, and a cadmium fume. An air exposed control group also was included. The rate of elimination of cadmium in the urine and feces, and the cadmium levels in selected tissues were measured at several intervals following the exposure. In addition, observations of the animals for clinical signs of toxicity and mortality and measurements of organ weights and body weight were performed. There was no mortality in the control, cadmium red or cadmium yellow exposed groups. In the cadmium carbonate exposed group, 3 out of 52 rats died, and in the cadmium fume exposed group, 25 out of 52 rats died. Cadmium blood levels indicated that cadmium from the cadmium carbonate and fume was absorbed to a greater degree than cadmium from the red and yellow pigments. The major route of elimination of cadmium following exposure to the two pigments was via the feces, with 80% being cleared within 24 hr. Elimination was slower following exposure to the carbonate. The levels of cadmium in the liver and kidneys were much higher following exposure to the carbonate than following exposure to the red and yellow pigments. It appeared that these cadmium compounds were not equivalent with respect to toxicity, absorption, distribution or excretion. Exposure to the two insoluble compounds, cadmium red and cadmium yellow, did not produce mortality and resulted in rapid elimination in the feces with lower tissue levels of cadmium than observed following exposure to the cadmium carbonate.

Inhalation toxicity studies with boron trifluoride.

An acute study of boron trifluoride (BF3) in rats indicated the 4-hr LC50 to be 1.21 mg/liter. In a 2-week study, all animals exposed to 180 mg/m3 died prior to the sixth exposure, rats exposed at concentrations of 66 and 24 mg/m3 showed clinical signs of respiratory irritation, body weight gain depressions, increased lung weights, and depressed liver weights. Histopathology showed necrosis and pyknosis of the proximal tubular epithelium of the kidneys. This effect was limited to the high-concentration exposure group. Based on the results of these studies, Fischer 344 rats were exposed 6 hr/day, 5 days/week for 13 weeks to a respirable, liquid aerosol of BF3 at concentrations of 0, 2.0, 6.0, and 17 mg/m3. One rat in the high exposure group died. The most significant finding in this group was necrosis of the proximal tubular epithelium of the kidneys. Other observations noted during the study included dried material around the nose and mouth, rales and excessive lacrimation, reversible depression of serum total protein and globulin concentrations, and increases in urinary, serum, and bone fluoride amounts. In the lower exposure groups, findings of respiratory irritation were minimal. All observations occurred in a dose-related pattern. Based on this study, exposure to BF3 at 17 mg/m3 resulted in renal toxicity, while exposure at 6 mg/m3, although showing elevations of fluoride amounts, did not result in a toxic response.

A method for repeated evaluation of benzene uptake in rats and mice during a six hour inhalation period.

Benzene uptake measurements and respiratory minute volume (RMV) were assessed in rats and mice during a 6-hour inhalation exposure to 300 ppm (v/v) of benzene vapor. The values for benzene uptake and RMV were used to compare predictions of inhaled dose in both species. The theoretical prediction assumed an unchanging RMV. The next prediction allowed adjustments for changes in RMV during exposure. The final prediction addressed benzene uptake directly. The uptake characteristics of benzene in both species were different from the theoretical prediction, from the prediction adjusted for changing RMV and from each other. The greatest difference was seen in rats where the observed benzene dose was only 28% of the theoretical value. The experiment was not designed to elucidate the causes for the difference between the predictions, nor was the data sufficient to suggest whether the rat or the mouse was a suitable model of benzene uptake in humans.

Toxicological evaluation of 1,1,1,2,2-pentafluoroethane (HFC-125).

Acute, subacute, and subchronic inhalation toxicity studies, developmental toxicity studies, a cardiac sensitization evaluation, and mutagenicity assays were conducted with pentafluoroethane (HFC-125). In the acute study, rats were exposed to a single concentration of 800,000 ppm for 4 hr. Ataxic gait and abnormal respiration were observed during exposure but not after exposure. There was no mortality or other signs of toxicity. Repeated exposures of rats to 50,000 ppm, 6 hr/day, 5 days/week for either 4 or 13 weeks elicited no effects on body weight, food consumption, clinical signs, hematology, biochemistry, urinalysis, organ weight, or tissue morphology. Positive evidence of cardiac sensitization in response to an intravenous epinephrine challenge in dogs was seen at 100,000 ppm and above, but not at 75,000 ppm. HFC-125 was not mutagenic in Salmonella typhimurium and Escherichia coli strains at concentrations of 20 to 100% (v/v) with and without activation. No evidence of clastogenic activity was observed in cultured Chinese hamster ovary (CHO) cells or human lymphocytes at < or = 70% HFC-125 when treatments were conducted for 3-4 hr with activation or for 24 and 48 hr (human lymphocytes only) without activation. However, a statistically significant increase in chromosomally aberrant cells was observed in CHO cells at 60% HFC-125 when treatment without activation was extended to 48 hr. The biological significance of this effect is questionable since signs of severe toxicity were also present. In vivo, no micronuclei were induced in mouse bone marrow at concentrations as high as 600,000 ppm HFC-125 for a 6-hr exposure. In addition, HFC-125 did not induce embryotoxic or teratogenic effects in either the rat or the rabbit at exposure concentrations as high as 50,000 ppm.