Biodistribution and acute toxicity of cadmium-free quantum dots with different surface functional groups in mice following intratracheal inhalation.

Indium phosphide/zinc sulfate (InP/ZnS) quantum dots (QDs) are presumed to be less hazardous than those that contain cadmium. However, the toxicological profile has not been established. The present study investigated the acute toxicity of InP/ZnS QDs with different surface modifications (COOH, NH2, and OH) in mice after pulmonary aerosol inhalation. InP/ZnS QDs were able to pass through the blood-gas barrier and enter the circulation, and subsequently accumulated in major organs. No obvious changes were observed in the body weight or major organ coefficients. Red blood cell counts and platelet-related indicators were in the normal range, but the proportion of white blood cells was altered. The InP/ZnS QDs caused varying degrees of changes in some serum markers, but no histopathological abnormalities related to InP/ZnS QDs treatment was observed in major organs except that hyperemia in alveolar septa was found in lung sections. These results suggested that the effects of respiratory exposure to InP/ZnS QDs on the lungs need to be fully considered in future biomedical application although the overall toxicity of quantum dots is relatively low.

Anticancer activity of a Gold(I) phosphine thioredoxin reductase inhibitor in multiple myeloma.

Multiple myeloma (MM), the second most common haematological malignancy, is a clonal plasma B-cell neoplasm that forms within the bone marrow. Despite recent advancements in treatment, MM remains an incurable disease. Auranofin, a linear gold(I) phosphine compound, has previously been shown to exert a significant anti-myeloma activity by inhibiting thioredoxin reductase (TrxR) activity. A bis-chelated tetrahedral gold(I) phosphine complex [Au(d2pype)2]Cl (where d2pype is 1,2-bis(di-2-pyridylphosphino)ethane) was previously designed to improve the gold(I) compound selectivity towards selenol- and thiol-containing proteins, such as TrxR. In this study, we show that [Au(d2pype)2]Cl significantly inhibited TrxR activity in both bortezomib-sensitive and resistant myeloma cells, which led to a significant reduction in cell proliferation and induction of apoptosis, both of which were dependent on ROS. In clonogenic assays, treatment with [Au(d2pype)2]Cl completely abrogated the tumourigenic capacity of MM cells, whereas auranofin was less effective. We also show that [Au(d2pype)2]Cl exerted a significant anti-myeloma activity in vivo in human RPMI8226 xenograft model in immunocompromised NOD/SCID mice. The MYC oncogene, known to drive myeloma progression, was downregulated in both in vitro and in vivo models when treated with [Au(d2pype)2]Cl. This study highlights the "proof of concept" that improved gold(I)-based compounds could potentially be used to not only treat MM but as an alternative tool to understand the role of the Trx system in the pathogenesis of this blood disease.

An assessment of vegetation management practices and burrow fumigation with aluminum phosphide as tools for managing voles within perennial crop fields in California, USA.

Voles (Cricetidae) cause extensive damage to a variety of crops throughout much of the Northern Hemisphere. The removal of vegetation from crop fields at the end of the growing season, combined with a subsequent burrow fumigant application of aluminum phosphide, has the potential to substantially curtail vole activity but has not been thoroughly examined. We set up a study to test the impact of these management tools in perennial globe artichoke (Cynara cardunculus var. scolymus) fields in Monterey County, CA, during 2010 and 2011, to determine their potential utility as part of an integrated pest management (IPM) program for managing California voles (Microtus californicus). We used both chewing indices and mortality estimates derived via radiotelemetry to assess the efficacy of aboveground vegetation removal and aluminum phosphide applications on vole abundance. We determined the impact of plowing artichoke fields on vole activity as well. Both removal of vegetation and applications of aluminum phosphide substantially reduced vole presence within treated fields. Plowing also reduced vole abundance to the point of little residual activity following treatment. These management practices appear to be effective at eliminating voles from crop fields. Combining these tools with management practices designed to slow down reinvasion by neighboring vole populations (e.g., barriers, repellents, traps) has the potential to substantially reduce farmer reliance on rodenticides for vole management, although rodenticides will still be needed to curtail populations that reestablish within crop fields. Such an IPM approach should substantially benefit both farmers and agro-ecosystems.

Fatal aluminum phosphide poisonings in Tirana (Albania), 2009 - 2013.

BACKGROUND: Acute poisonings particularly through pesticides have become a major public health concern in Albania during the last decade. FINDINGS: The number of fatalities due to aluminum phosphide intoxications was more than doubled during a five year-period from 2009 to 2013, and a cluster of suicides perpetrated with Phostoxin was registered. Several factors are accountable for such a phenomenon, including the fact that aluminum phosphide agents are freely available in the Albanian market, their price is extremely low and they are sold without any legal restriction. The mass media unfortunately warranted an emulating effect to dramatic intoxications, which gained by such means the notoriety of a secure lethal weapon. CONCLUSIONS: Our experience with more than three hundred intoxications with aluminum phosphide agents in the last five years, showed that a considerable delay from the moment of exposure (mainly through ingestion) to specialized medical help seeking, created a considerable obstacle for a successful treatment of cases, and eventually for the survival of patients. The lack of a specific antidote adds further challenges to all these exposures. The need for public health policies aiming at prevention, awareness, and possibly the substitution of Phostoxin or other aluminum phosphide pesticides with less dangerous agents is formulated.

Ingestion of gallium phosphide nanowires has no adverse effect on Drosophila tissue function.

Engineered nanoparticles have been under increasing scrutiny in recent years. High aspect ratio nanoparticles such as carbon nanotubes and nanowires have raised safety concerns due to their geometrical similarity to asbestos fibers. III-V epitaxial semiconductor nanowires are expected to be utilized in devices such as LEDs and solar cells and will thus be available to the public. In addition, clean-room staff fabricating and characterizing the nanowires are at risk of exposure, emphasizing the importance of investigating their possible toxicity. Here we investigated the effects of gallium phosphide nanowires on the fruit fly Drosophila melanogaster. Drosophila larvae and/or adults were exposed to gallium phosphide nanowires by ingestion with food. The toxicity and tissue interaction of the nanowires was evaluated by investigating tissue distribution, activation of immune response, genome-wide gene expression, life span, fecundity and somatic mutation rates. Our results show that gallium phosphide nanowires applied through the diet are not taken up into Drosophila tissues, do not elicit a measurable immune response or changes in genome-wide gene expression and do not significantly affect life span or somatic mutation rate.

Inhalation of phosphine gas following a fire associated with fumigation of processed pistachio nuts.

On December 10, 2009, a fumigation stack containing aluminum phosphide became soaked with rain water and caught fire at a pistachio processing plant in Kern County, California. Untrained plant personnel responding to the fire had exposure to pyrolysis by-products, particulates, and extinguisher ingredients. Ten workers taken for medical evaluation had respiratory and nonspecific systemic symptoms consistent with exposure to phosphine gas. Six of the 10 workers had respiratory distress, indicated by chest pain, shortness of breath, elevated respiratory rate, or decreased oxygen saturation. Recommendations are made for the management of similar illnesses and prevention of similar exposures.

Protective effects of N-acetylcysteine on aluminum phosphide-induced oxidative stress in acute human poisoning.

OBJECTIVE: Aluminum phosphide is used as a fumigant. It produces phosphine gas (PH3). PH3 is a mitochondrial poison which inhibits cytochrome c oxidase, it leads to generation of reactive oxygen species; so one of the most important suggested mechanisms for its toxicity is induction of oxidative stress. In this regard, it could be proposed that a drug like N-acetylcysteine (NAC) as an antioxidant would improve the tolerance of aluminum phosphide-intoxicated cases. The objective of this study was to evaluate the protective effects of NAC on acute aluminum phosphide poisoning. METHODS: This was a prospective, randomized, controlled open-label trial. All patients received the same supportive treatments. NAC treatment group also received NAC. The blood thiobarbituric acid reactive substances as a marker of lipid peroxidation and total antioxidant capacity of plasma were analyzed. RESULTS: Mean ingested dose of aluminum phosphide in NAC treatment and control groups was 4.8 ± 0.9 g vs. 5.4 ± 3.3 g, respectively (p = 0.41). Significant increase in plasma malonyldialdehyde level in control group was observed (139 ± 28.2 vs. 149.6 ± 35.2 µmol/L, p = 0.02). NAC infusion in NAC treatment group significantly decreased malondialdehyde level (195.7 ± 67.4 vs. 174.6 ± 48.9 µmol/L, p = 0.03), duration of hospitalization (2.7 ± 1.8 days vs. 8.5 ± 8.2 days, p = 0.02), rate of intubation and ventilation (45.4% vs. 73.3%, p = 0.04). Mortality rate in NAC treatment and control groups were 36% and 60%, respectively with odds ratio 2.6 (0.7-10.1, 95% CI). CONCLUSION: NAC may have a therapeutic effect in acute aluminum phosphide poisoning.

Comparative cytotoxicity of gold-doxorubicin and InP-doxorubicin conjugates.

Direct comparisons of different types of nanoparticles for drug delivery have seldom been performed. In this study we compare the physical properties and cellular activity of doxorubicin (Dox) conjugates to gold nanoparticles (Au) and InP quantum dots of comparable diameter. Although the Au particles alone are non-toxic and InP is moderately toxic, Au-Dox is more effective than InP-Dox against the Dox-resistant B16 melanoma cell line. Light exposure does not augment the efficacy of InP-Dox, suggesting that conjugates are breaking down. Electron and confocal microscopy and atomic absorption spectroscopy reveal that over 60% of the Au-Dox conjugates reach the cell nucleus. In contrast, InP-Dox enters cell nuclei to a very limited extent, although liberated Dox from the conjugates does eventually reach the nucleus. These observations are attributed to faster Dox release from Au conjugates under endosomal conditions, greater aggregation of InP-Dox with cytoplasmic proteins, and adherence of InP to membranes. These findings have important implications for design of active drug-nanoparticle conjugates.

Residue formations of phosphorus hydride polymers and phosphorus oxyacids during phosphine gas fumigations of stored products.

With the extent of international usage and the critical role phosphine gas (PH3) plays in commercial pest control, identification of the residual components deposited during fumigation is mandatory. It has been postulated that these infrequent residues are primarily composed of phosphoric acid or reduced forms of phosphoric acid [hypophosphorous acid (H3PO2) and phosphorous acid (H3PO3)], due to the oxidative degradation of phosphine. Using environmental scanning electron microscopy, gas phase Fourier transform infrared spectroscopy, and X-ray fluorescence spectroscopy, the structural elucidation and formation mechanism of the yellow amorphous polyhydric phosphorus polymers (P(x)H(y)) that occur in addition to the lower oxyacids of phosphorus in residues deposited during PH3 fumigations of select tobacco commodities are explored. This research determined that nitric oxide gas (or nitrogen dioxide) initiates residue formation of phosphorus hydride polymers and phosphorus oxyacids during PH3 fumigations of stored products.

Comparative toxicity of fumigants and a phosphine synergist using a novel containment chamber for the safe generation of concentrated phosphine gas.

BACKGROUND: With the phasing out of ozone-depleting substances in accordance with the United Nations Montreal Protocol, phosphine remains as the only economically viable fumigant for widespread use. However the development of high-level resistance in several pest insects threatens the future usage of phosphine; yet research into phosphine resistance mechanisms has been limited due to the potential for human poisoning in enclosed laboratory environments. PRINCIPAL FINDINGS: Here we describe a custom-designed chamber for safely containing phosphine gas generated from aluminium phosphide tablets. In an improvement on previous generation systems, this chamber can be completely sealed to control the escape of phosphine. The device has been utilised in a screening program with C. elegans that has identified a phosphine synergist, and quantified the efficacy of a new fumigant against that of phosphine. The phosphine-induced mortality at 20 degrees C has been determined with an LC(50) of 732 ppm. This result was contrasted with the efficacy of a potential new botanical pesticide dimethyl disulphide, which for a 24 hour exposure at 20 degrees C is 600 times more potent than phosphine (LC(50) 1.24 ppm). We also found that co-administration of the glutathione depletor diethyl maleate (DEM) with a sublethal dose of phosphine (70 ppm,

Worker exposure standard for phosphine gas.

The 1998 U.S. Environmental Protection Agency Office of Pesticide Programs (OPP) re-registration eligibility decision (RED) for phosphine fumigants has generated much interest in defining safe levels of exposure for workers and worker bystanders. This report summarizes the pertinent literature on phosphine toxicity, including animal inhalation studies and human epidemiology studies, and also describes a margin-of-exposure (MOE) analysis based on available worker exposure data. In addition, a safe occupational exposure limit is estimated using typical OPP assumptions, after determination of appropriate uncertainty factors, based on quality of data in the principal study and pharmacokinetic considerations. While a conservative 8-hour time-weighted average (TWA) of 0.1 ppm was calculated, the overall weight of evidence, from a risk-management perspective, supports a conclusion that an occupational TWA of 0.3 ppm provides adequate health protection. In addition, a 15-minute short-term exposure limit (STEL) of 3 ppm was estimated. Finally, in contrast to the MOE analysis described in the OPP's phosphine RED, the MOE analysis described herein does not indicate that fumigation workers are currently being exposed to unacceptable levels of phosphine. Collectively, these findings support the occupational exposure limits of 0.3 ppm (8-hour TWA) and 1 ppm (STEL) established in the updated applicator's manuals for phosphine-generating products, which recently received approval from OPP.

The role of oxidative stress in indium phosphide-induced lung carcinogenesis in rats.

Indium phosphide (IP), widely used in the microelectronics industry, was tested for potential carcinogenicity. Sixty male and 60 female Fischer 344 rats were exposed by aerosol for 6 h/day, 5 days/week, for 21 weeks (0.1 or 0.3 mg/m(3); stop exposure groups) or 105 weeks (0 or 0.03 mg/m(3) groups) with interim groups (10 animals/group/sex) evaluated at 3 months. After 3-month exposure, severe pulmonary inflammation with numerous infiltrating macrophages and alveolar proteinosis appeared. After 2 years, dose-dependent high incidences of alveolar/bronchiolar adenomas and carcinomas occurred in both sexes; four cases of squamous cell carcinomas appeared in males (0.3 mg/m(3)), and a variety of non-neoplastic lung lesions, including simple and atypical hyperplasia, chronic active inflammation, and squamous cyst, occurred in both sexes. To investigate whether inflammation-related oxidative stress functioned in the pathogenesis of IP-related pulmonary lesions, we stained lungs of control and high-dose animals immunohistochemically for four markers indicative of oxidative stress: inducible nitric oxide synthase (i-NOS), cyclooxygenase-2 (COX-2), glutathione-S-transferase Pi (GST-Pi), and 8-hydroxydeoxyguanosine (8-OHdG). Paraffin-embedded samples from the 3-month and 2-year control and treated females were used. i-NOS and COX-2 were highly expressed in inflammatory foci after 3 months; at 2 years, all four markers were expressed in non-neoplastic and neoplastic lesions. Most i-NOS staining, mainly in macrophages, occurred in chronic inflammatory and atypical hyperplastic lesions. GST-Pi and 8-OHdG expression occurred in cells of carcinoma epithelium, atypical hyperplasia, and squamous cysts. These findings suggest that IP inhalation causes pulmonary inflammation associated with oxidative stress, resulting in progression to atypical hyperplasia and neoplasia.

Toxicology and carcinogenesis studies of indium phosphide (CAS No. 22398-90-7) in F344/N rats and B6C3F1 mice (inhalation studies).

Indium phosphide is used to make semiconductors,injection lasers, solar cells, photodiodes, and light-emittingdiodes. Indium phosphide was nominated for study because of its widespread use in the microelectronics industry, the potential for worker exposure,and the absence of chronic toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to indium phosphide (greater than 99% pure) by inhalation for 14 weeks or 2 years. The frequency of micronuclei was determined in the peripheral blood of mice exposed to indium phosphide for 14 weeks. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to particulate aerosols of indium phosphide with amass median aerodynamic diameter of approximately 1.2 microm at concentrations of 0, 1, 3, 10, 30, or 100 mg/m3 by inhalation, 6 hours per day, 5 days per week (weeks 1 through 4 and weeks 10 through 14) or 7 days per week (weeks 5 through 9) to accommodate a concurrent teratology study. One male in the 100 mg/m3 group died before the end of the study. Body weight gains of all males and females exposed to 100 mg/m3 were less than those of the chamber controls. As a result of indium phosphide exposure, the lungs of all exposed rats had a gray to black discoloration and were significantly enlarged, weighing 2.7- to 4.4-fold more than those of the chamber controls. Indium phosphide particles were observed throughout the respiratory tract and in the lung-associated lymph nodes. A spectrum of inflammatory and proliferative lesions generally occurred in the lungs of all exposed groups of rats and consisted of alveolar proteinosis, chronic inflammation, interstitial fibrosis, and alveolar epithelial hyperplasia. Pulmonary inflammation was attended by increased leukocyte and neutrophil counts in the blood. The alveolar proteinosis was the principal apparent reason for the increase in lung weights. Indium phosphide caused inflammation at the base of the epiglottis of the larynx and hyperplasia of the bronchial and mediastinal lymph nodes. Exposure to indium phosphide affected the circulating erythroid mass. It induced a microcytic erythrocytosis consistent with bone marrow hyperplasia and hematopoietic cell proliferation of the spleen. Hepatocellular necrosis was suggested by increased serum activities of alanine aminotransferase and sorbitol dehydrogenase in all exposed groups of males and in 10 mg/m3 or greater females and was confirmed microscopically in 100 mg/m3 males and females. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to particulate aerosols of indium phosphide with a mass median aerodynamic diameter of approximately 1.2 microm at concentrations of 0, 1, 3, 10, 30, or 100 mg/m3 by inhalation, 6 hours per day, 5 days per week (weeks 1 through 4 and weeks 10 through 14)or 7 days per week (weeks 5 through 9). Although the effects of indium phosphide exposure were similar in rats and mice, mice were more severely affected in that all males and females in the 100 mg/m3 groups either died or were removed moribund during the study. One male and three females in the 30 mg/m3 group were also removed before the end of the study. In general, body weight gains were significantly less in males and females exposed to 3 mg/m3 or greater compared to those of the chamber controls. Mice exposed to 30 or 100 mg/m3 were lethargic and experienced rapid, shallow breathing. As in rats, lungs were discolored and enlarged 2.6- to 4.1-fold greater than those of chamber controls due to the exposure-induced alveolar proteinosis. Indium phosphide particles were observed in the nose, trachea,larynx, and lymph nodes of some exposed males and females. Alveolar proteinosis, chronic active inflammation,interstitial fibrosis, and alveolar epithelial hyperplasia were observed; these effects were more severe than in rats. Hyperplasia in the bronchial lymph nodes and squamous metaplasia, necrosis, and suppurative inflammation of the larynx were observed in some exposed males and females. Exposure to indium phosphide induced a microcytic erythrocytosis which was consistent with the observed hematopoietic cell proliferation of the spleen.2-YEAR STUDY IN RATS Groups of 60 male and 60 female rats were exposed to particulate aerosols of indium phosphide at concentrations of 0, 0.03, 0.1, or 0.3 mg/m3, 6 hours per day,5 days per week, for 22 weeks (0.1 and 0.3 mg/m3 groups) or 105 weeks (0 and 0.03 mg/m3 groups). Animals in the 0.1 and 0.3 mg/m3 group were maintained on filtered air from exposure termination at week 22 until the end of the studies. Ten males and 10 females per group were evaluated at 3 months. 3-Month Interim Evaluation: Exposure to indium phosphide for 3 months caused a microcytic erythrocytosis and also caused enlarged lungs and lesions in the respiratory tract and lung associated lymph nodes. Although qualitatively similar to those observed in the 14-week studies, these effects were considerably less severe. However, the lesions in the lungs of rats exposed to 0.1 or 0.3 mg/m3 were considered sufficiently severe that exposure was discontinued in these groups, and the groups were allowed to continue unexposed for the remainder of the study. Survival, Body Weights, and Clinical Findings: Exposure to indium phosphide had no effect on survival or body weight gain. During the last 6 months of the study, rats in the 0.03 and 0.3 mg/m3 groups became lethargic and males breathed abnormally. Pathology Findings: At 2 years, exposure to indium phosphide caused increased incidences of alveolar/bronchiolar adenomas and carcinomas in rats. Squamous cell carcinoma of the lung occurred in four male rats exposed to 0.3 mg/m3. As observed in the 14-week study and at the 3-month interim evaluation, a spectrum of inflammatory and proliferative lesions of the lung were observed in all exposed groups of males and females;however, the extent and severity of the lesions were generally greater and included atypical hyperplasia,chronic inflammation, alveolar epithelial hyperplasia and metaplasia, alveolar proteinosis, and interstitial fibrosis. Exposure to indium phosphide also caused increased incidences of benign and malignant pheochromocytomas of the adrenal gland in males and females. Marginal increases in the incidences of mononuclear cell leukemia in males and females, fibroma of the skin in males, and carcinoma of the mammary gland in females may have been related to exposure to indium phosphide. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were exposed to particulate aerosols of indium phosphide at concentrations of 0, 0.03, 0.1, or 0.3 mg/m3, 6 hours per day,5 days per week, for 21 weeks (0.1 and 0.3 mg/m3 groups) or 105 weeks (0 and 0.03 mg/m3 groups). Animals in the 0.1 and 0.3 mg/m3 groups were maintained on filtered air from exposure termination at week 21 until the end of the studies. Ten males and 10 females per group were evaluated at 3 months. 3-Month Interim Evaluation:Exposure to indium phosphide for 3 months affected the circulating erythroid mass and caused enlarged lungs and lesions in the respiratory tract and lung associated lymph nodes. These effects, although qualitatively similar to those observed in the 14-week studies, were considerably less severe. However, the lesions in the lungs of mice exposed to 0.1 mg/m3 and greater were considered sufficiently severe that exposure was discontinued in these groups and the groups were allowed to continue unexposed for the remainder of the study. Survival and Body Weights: In general, exposure to indium phosphide for 2 years reduced survival and body weight gain in exposed males and females. Pathology Findings:At 2 years, exposure to indium phosphide caused increased incidences of alveolar/bronchiolar carcinomas in males and alveolar/bronchiolar adenomas and carcinomas in females. In addition to the alveolar proteinosis and chronic active inflammation seen at earlier time points, serosa fibrosis and pleural mesothelial hyperplasia were also present. The incidences of hepatocellular neoplasms were also significantly increased in exposed males and females. Exposed groups of males and females had increased incidences of eosinophilic foci of the liver at 2 years. Marginal increases in the incidences of neoplasms of the small intestines in male mice may have been related to exposure to indium phosphide. Exposure to indium phosphide also caused inflammation of the arteries of the heart, primarily the coronary arteries and the proximal aorta, and to a lesser extent the lung-associated lymph nodes in males and in females. TISSUE BURDEN ANALYSES: Deposition and clearance studies of indium following long term exposure of rats and mice to indium phosphide by inhalation were performed. Although there were quantitative differences in lung burden and kinetic parameters for rats and mice, qualitatively they were similar. Deposition of indium in the lungs appeared to follow a zero-order (constant rate) process. Retained lung burdens throughout the studies were proportional to exposure concentration and duration. No differences in elimination rates of indium from the lungs were observed as a function of exposure concentration in either rats or mice. These studies indicated that elimination of indium was quite slow. Mice exhibited clearance half-times of 144 and 163 days for the 0.1 and 0.3 mg/m3 groups, respectively, as compared to 262 and 291 days for rats exposed to the same concentrations. The lung deposition and clearance model was used to estimate the total amount of indium deposited in the lungs of rats and mice after exposure to 0.03 mg/m3 for 2 years or to 0.1 or 0.3 mg/m3 for 21 or 22 weeks, the lung burdens at the end of the 2-year study, and the area under lung burden curves (AUC). For both species, estimates at the end of 2 years indicated that the lung burdens in the continuously exposed 0.03 mg/m3 groups were greater than those in the 0.1 or 0.3 mg/m3 groups.(ABSTRACT TRUNCATED)

A 2-year inhalation study of phosphine in rats.

Phosphine is a highly toxic gas used as a fumigant, a dopant in semiconductor manufacturing, and in the production of organophosphines. In a chronic toxicity and oncogenicity study of phosphine, 60 male and female F344 rats per group were exposed via whole-body inhalation for 6 h/day, 5 days/wk for up to 104 wk to mean concentrations of 0, 0.3, 1, or 3 ppm phosphine. Three parts per million was considered the maximum exposure level because of lethality seen at higher exposure levels in previous repeat dose studies. Ten rats per sex per group were sacrificed after 52 wk of exposure. Survivors were sacrificed after 104 wk of exposure. There were no phosphine-related effects seen on clinical observations, body weight, food consumption, hematology, clinical chemistry, urinalysis, or ophthalmology. There were no phosphine-related macroscopic findings or effect on absolute or relative organ weights. No histomorphologic alterations attributable to phosphine exposure were seen. In conclusion, under the conditions of this study, there were no treatment-related changes suggestive of a toxic or carcinogenic effect seen in rats following 52 wk or 2 yr of whole-body inhalation exposure to 0.3, 1, or 3 ppm phosphine.

Cytogenetic and germ cell effects of phosphine inhalation by rodents: II. Subacute exposures to rats and mice.

Phosphine (PH3) is a highly toxic grain fumigant to which there is significant human workplace exposure. To determine the in vivo cytogenetic effects of inhalation of PH3, male F344/N rats and B6C3F1 mice were exposed to target concentrations of 0, 1.25, 2.5, or 5 ppm PH3 for 6 hr/day for 9 days over an 11-day period. Approximately 20 hr after the termination of exposures, blood was removed from the mice and rats by cardiac puncture and the lymphocytes cultured for analyses of sister chromatid exchanges and chromosome aberrations in rats and mice, and micronuclei (MN) in cytochalasin B-induced binucleated lymphocytes from mice. In addition, bone marrow (rats) and peripheral blood (mice) smears were made for the analysis of MN in polychromatic and normochromatic erythrocytes. No significant increase in any of the cytogenetic endpoints was found at any of the concentrations examined. These results indicate that concentrations of PH3 up to 5 ppm are not genotoxic to rodents when administered by inhalation for 9 days during an 11-day period as measured by several cytogenetic assays. To evaluate the effects of PH3 on male germ cells, a dominant lethal test was conducted in male mice exposed to 5 ppm PH3 for 10 days over a 12-day period and mated to groups of untreated females (2 females/male) on each of 6 consecutive 4-day mating intervals. None of the 6 groups of females exhibited a significant increase in percent resorptions. These results indicate that exposure to 5 ppm PH3 by inhalation does not induce dominant lethality in male mouse germ cells at steps in spermatogenesis ranging from late differentiating spermatogonia/early primary spermatocytes through mature sperm.

[Combined chronic toxicity/carcinogenicity test of tris(2-chloroethyl)phosphate (TCEP) applied to female mouse skin].

Tris(2-chloroethyl)phosphate (TCEP), a widely used flame retardant, was tested for its skin chronic toxicity/carcinogenicity using female Slc: ddY mice. TCEP (5 and 50%) dissolved in ethanol was applied to the shaved skin twice a week for 79 weeks. The control group received ethanol under similar condition. In addition, 5 animals in each group were killed at 6 and 12 months and used for the chronic toxicity study. In body weight, food consumption and survival rate, there was no significant difference between the control and treated groups. Spleen weight was decreased in the 50% group. No significant difference in the incidence of tumors and other non-neoplastic lesions of the skin and other organs was found between the control and treated groups. The results indicate that under the conditions of the present study, TCEP has no carcinogenicity and toxicity for the skin.