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PubMed1983

Evaluation of the association between birth defects and exposure to ambient vinyl chloride.

Birth defects incidence for infants born to residents of Shawinigan, Canada in 1966-1979 were significantly higher than in three comparison communities. Since there has been a vinyl chloride polymerization plant in this town since 1943 from which ten cases of angiosarcoma of the liver have been identified, this study explores the possible association between exposure to vinyl chloride monomer (VCM) in ambient air and the occurrence of birth defects in the community. The excess of birth defects fluctuated seasonally in a way that corresponded to changes in VCM concentration in the environment. Mothers who gave birth to malformed children were younger on average in Shawinigan than in the comparison communities. However, there was no excess of still-births in Shawinigan. The excess in birth defects involved most organ systems, and variation in birth-defect rates among school districts could not be accounted for by estimates of VCM in the atmosphere. The occupational and residential histories of parents who gave birth to malformed infants were compared with those of parents of normal infants. The two groups did not differ in occupational exposure or closeness of residence to the vinyl chloride polymerization plant. Some descriptive data from this study raised the hypothesis of an association between VCM in the air and birth defects in the exposed community, but as a whole, within the sample size available, such an association could not be substantiated.

Abnormalities, Drug-Induced↗
PubMed2004

Physical and chemical aspects of long-term biodeterioration of some polymers and composites.

A biodeterioration study was performed on synthetic polymeric materials including homogenous film made from poly(tetrafluorine ethylene), copolymer film made from tetrafluorine ethylene and perfluoromethyl vinyl ether, vulcanized rubber containing natural caoutchouc, and vulcanized rubber, the main component of which was synthetic butadiene nitrile caoutchouc. The materials were exposed for 12 years to the open air, in mycological containers, and in a cellar in maritime climate conditions: air humidity 72%-90% and seasonal average temperature of 17 degrees C in summer and -2.5 degrees C in winter. The studies of optical and electron microscopy revealed that microorganisms were able to develop not only on the surface of the materials but also to penetrate inside into deeper layers. The fungi that produced the most intensive deterioration in the fluorine polymers and vulcanized rubbers belonged to the Alternaria, Aspergillus, Aureobasidium, Cladosporium, Penicillium, Oidiodendron and Trichoderma genera. The fungi Aspergillus fumigatus, A. niger, Aureobasidium pullulans, and Trichoderma viride produced the most intensive deterioration in the fluorine films, whereas Alternaria tenuissima, Cladosporium herbarum, C. sphaerospermum, and fungi of the Oidiodendron genus were widespread on vulcanized rubbers. Fungi of the Aspergillus and Penicillium genera prevailed on both fluorine films and rubbers exposed in a cellar. Infrared spectroscopy indicated that the structures of poly(tetrafluorine ethylene) and the copolymer of tetrafluorine ethylene and perfluoromethyl vinyl ether did not change after the 12-year exposure; only insignificant changes in surface morphology were observed by optical microscopy. Vulcanized rubber made both from natural and from synthetic caoutchouc exposed for the same length of time showed rather evident changes in appearance and structure. X-ray graphical analysis revealed that new crystallization of the caoutchouc and a possible change in chemical composition of the fillers had occurred.

Biodegradation, Environmental↗
PubMed1993

High-resolution liquid chromatography of oligonucleotides on nonporous alkylated styrene-divinylbenzene copolymers.

Phosphodiester-oligonucleotides were separated by ion-pair reversed-phase HPLC on nonporous polystyrene-based particles having a diameter of 2.1 +/- 0.12 microns. With unmodified poly(styrene-divinylbenzene) beads it was not possible to resolve oligonucleotides efficiently. However, upon addition of polyvinyl alcohol during polymerization baseline resolution of phosphorylated oligodeoxyadenylic acids with a chain length of up to 30 bases was obtained, with triethylammonium acetate serving as ion-pairing reagent. An even higher separation efficiency was achieved by Friedel-Crafts alkylation of poly(styrene-divinylbenzene) particles. At a column temperature of 50 degrees C, the number of theoretical plates exceeded 6 x 10(5) per meter. The maximum loading capacity for a 50 x 4.6-mm i.d. column still resulting in the highest resolution was 0.1 microgram. Calibration curves showed excellent linearity over a range of at least 4 magnitudes, with a lower mass detection limit of 0.16 ng. Recoveries ranged from 96.7 to 100.8%. The same stationary phase also allowed the separation of phosphorylated from dephosphorylated oligonucleotides, the former ones being eluted earlier.

Alkylation↗
PubMed1999

A turbidimetric assay for quantitating functional fibrin(ogen) using polystyrene-divinylbenzene microparticles.

A sensitive assay has been developed to quantitate fibrinogen in plasma or in other aqueous solutions. Microscopic latex particles, modified with a mixed monomolecular film of lecithin and fibrinogen, are used as a solid-phase reagent. These lecithin/fibrinogen-coated beads aggregate when stirred in the presence of thrombin and, when solution-phase fibrinogen is added, the increased rate of aggregation is proportional to the concentration of soluble fibrinogen. Using a sample volume of 200 microl, as little as 15 nM ( approximately 5 microg ml-1) fibrinogen can be measured. Fibrinogen determinations using the bead assay compared favorably with those derived from a standard clinical assay, with a correlation coefficient (r2) of 0.9710 over a range of 2.5 to 28.0 microM. Analytic precision was comparable to available assays, with typical coefficients of variation of 12.7 and 7.1% for fibrinogen concentrations of 30 nM and 15.0 microM, respectively. The method has a dynamic range of 15 nM to over 3.0 microM and offers the advantage of being sensitive to 20-fold lower concentrations of fibrinogen compared to routine clot-based methods. Unlike immunological assays, e.g., ELISA, it measures only the functional protein. This bead method should prove to be of greatest use to investigators measuring low levels of functional fibrin(ogen).

Enzyme-Linked Immunosorbent Assay↗
PubMed1994

Chronic toxicity and oncogenicity inhalation study with vinyl acetate in the rat and mouse.

Vinyl acetate was evaluated for chronic toxicity and oncogenicity in male and female rats and mice in a 104-week study. Target concentrations were 0, 50, 200, and 600 ppm. The study included interim terminations at approximately 53 and 83 weeks and a group whose exposure was terminated at 70 weeks and allowed a 15-week recovery period. Over the course of the exposures, body weight gain was consistently depressed in all 600 ppm groups and in the 200 ppm mice. Except for female rats of the 600 ppm exposure group, recovery animals showed significant improvements in weight gain relative to controls. There were no changes in hematological parameters of either species that could be unequivocally related to treatment. The only effect noted on clinical chemical parameters during the study were decreases in blood glucose in the 600 ppm females. There were no adverse effects on survival in either species. Increases in lung weight were noted in rats and mice primarily in the 600 ppm groups. These changes were associated with bronchial exfoliation, macrophage accumulation, and fibrous plaques and buds extending into the airway lumen, and bronchial/bronchiolar epithelial disorganization. The most significant histopathological changes were noted in the nasal cavity. In the olfactory epithelium of both rats and mice, the main nonneoplastic changes included epithelial atrophy, regenerative effects (squamous metaplasia and respiratory metaplasia of olfactory epithelium), basal cell hyperplasia, and epithelial nest-like infolds. No nonneoplastic changes were observed in the respiratory epithelium of rats, while squamous metaplasia at the naso/maxilloturbinate region was prevalent in mice. Nonneoplastic changes were similar in the recovery groups. Oncogenic responses to vinyl acetate exposure were mainly confined to the nasal cavity in rats and included endo- and exophytic papillomas, squamous cell carcinoma, carcinoma in situ in olfactory regions, and endophytic papilloma in respiratory regions. Squamous cell carcinomas were also found either in areas normally covered by cuboidal epithelium or areas of unknown origin. One squamous cell carcinoma was found in the larynx of a rat of the 600 ppm groups. One squamous cell carcinoma was found in the lung of a mouse of the 600 ppm group.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗
PubMed1995

Developmental toxicity of oral and inhaled vinyl acetate in the rat.

Vinyl acetate (VA) is used almost exclusively as an industrial chemical in polymerization, copolymerization, or as a chemical intermediate. The present studies were undertaken as part of a collaborative effort by the VA producers of Western Europe, Japan, and the United States to provide animal toxicology data for risk assessment. To assess the potential of VA causing developmental toxicity in rodents, groups of 23 or 24 Crl:CD(SD)BR rats were given 0, 200, 1000, or 5000 ppm VA in drinking water or exposed 6 hr/day to 0, 50, 200, or 1000 ppm VA vapors on Days 6-15 of gestation (both routes approximately 0, 25, 100, or 500 mg/kg/day). Administration of VA in the drinking water produced no evidence of maternal or developmental toxicity. A significantly lowered water intake was observed in dams from the 5000 ppm VA group and probably reflected unpalatability of the VA water solution at the highest dose level. In the inhalation study, maternal toxicity was evident by a marked reduction in weight gain of dams exposed to 1000 but not 200 or 50 ppm VA. Fetal toxicity was evident by a statistically significant decrease in mean fetal weight and mean crown-rump length in fetuses from the 1000-ppm VA group. In addition, there was a statistically significant increase in the incidence of minor skeletal alterations in fetuses from dams exposed to 1000 ppm VA. Delayed ossification was the main skeletal alteration. In summary, pregnant rats were relatively insensitive to the effects of VA administered in the drinking water at a concentration level as high as 5000 ppm. However, VA did adversely affect both the dam and the conceptus at an inhaled concentration of 1000 ppm, but not at lower exposure levels. These results indicate that VA is not uniquely toxic to the conceptus. The no-observed-effect level for the dam and conceptus under these experimental conditions was greater than 5000 ppm for the drinking water study and was 200 ppm for the inhalation study.

Abnormalities, Drug-Induced↗
PubMed1995

A two-generation reproduction study in rats receiving drinking water containing vinyl acetate.

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

Administration, Oral↗
PubMed1995

Inhalation oncogenicity bioassay in rats and mice with vinyl fluoride.

The purpose of this study was to assess the oncogenic potential of vinyl fluoride in rats and mice when administered by inhalation. Male and female rats and mice were exposed to 0, 25, 250, or 2500 ppm vinyl fluoride 6 hr per day, 5 days per week, for 2 years (rats) or 18 months (mice). Slight body weight gain decrements were noted in groups of vinyl fluoride-exposed rats and mice. No significant clinical signs of toxicity were noted other than an increase in the incidence of palpable masses in the region of the mammary gland in female mice exposed to vinyl fluoride. Survival was decreased in male rats and mice of the 250 and 2500 ppm groups and female rats and mice of all vinyl fluoride-exposed groups compared to controls. Urinary fluoride excretion, an indicator of vinyl fluoride metabolism, increased with concentration and time although the dose relationship appeared to plateau at concentrations > or = 250 ppm. Gross observations made at necropsy of rats supported histological observations of hepatic hemangiosarcoma, hepatocellular adenoma and carcinoma, hepatic foci of clear cell and basophilic alteration, hepatic sinusoidal dilatation, metastatic lung tumors, and Zymbal's gland tumors. Hepatic hemangiosarcoma was the sentinel lesion in rats. Gross observations made at necropsy of mice supported histological observations of bronchioloalveolar adenoma and hyperplasia, hepatic hemangiosarcoma and hepatocellular hyperplasia with angiectasis and peliosis, and mammary gland adenocarcinoma and hyperplasia. Bronchioloalveolar adenoma appeared to be the sentinel lesion in mice. The spectrum of vinyl fluoride-induced tumors is similar to that induced by other monohaloethylenes in rats and mice. Under the conditions of this study, vinyl fluoride was carcinogenic in male and female rats and mice at concentrations greater than or equal to 25 ppm.

Administration, Inhalation↗
PubMed1997

Toxicity of divinylbenzene-55 for B6C3F1 mice in a two-week inhalation study.

Divinylbenzene (DVB) is a crosslinking monomer used primarily for copolymerization with styrene to produce ion-exchange resins. The toxicity of inhaled DVB was investigated because of the potential for worker exposure and the structural similarity of DVB to styrene, a potential carcinogen. Male and female B6C3F1 mice were exposed to 0, 25, 50, or 75 ppm DVB for 6 hr/day, 5 days/week for up to 2 weeks. Six mice/sex/dose group were killed after 3, 5, and 10 exposures and six mice/sex in the 75 ppm group were killed 7 days after 10 exposures. The most severe effects occurred in the nasal cavity and liver, with less severe effects occurring in the kidneys. In the nasal cavity olfactory epithelium acute necrosis and inflammation were present at early time points followed by regeneration, architectural reorganization, and focal respiratory metaplasia by 7 days after the last exposure. Olfactory epithelial changes were concentration-dependent with extensive involvement at 75 ppm and peripheral sparing at 25 ppm. There was also necrosis and regeneration of olfactory-associated Bowman's glands as well as the lateral nasal (Steno's) glands. Hepatocellular centrilobular (CL) necrosis was observed only in the 75 ppm dose group and was similar to that caused by styrene. A time-dependent progression was observed, characterized by CL degeneration after 1 exposure, necrosis after 3 and 5 exposures, and chronic inflammation with CL karyomegaly after 10 exposures and 7 days after the 10th exposure. Hepatic GSH levels were decreased in a dose-dependent manner. In the kidneys, transient tubular damage was observed in some male mice exposed to 75 ppm, and appeared to be a response to DVB-induced tubular epithelial injury.

Administration, Inhalation↗
PubMed1993

Development and implementation of a safety evaluation program for chemical fibers.

Polyester and acrylic fibers often have prolonged contact with human skin: the sucking of childrens' toys may lead to ingestion. During manufacture, occupational exposure to fiber components may occur. An evaluation of these possible hazards was undertaken by data appraisal, chemical analyses, and animal plus human testing. Occupational exposure limits have already been set for the chemicals used in polymer manufacture. Finishing agents (applied to the fibers) were examined in bacterial mutation and rat acute oral toxicity tests. Finished fibers were tested for acute toxicity and then for sensitizing potential (on guinea pig skin). Human volunteer trials for skin irritance and sensitization followed. No adverse reactions were seen. Only when fibers were burnt was toxicity seen: smoke from acrylic fiber proved more toxic than that from polyester fiber (due principally to hydrogen cyanide release). Migration tests showed that little material leached out from the fibers: < 1 mg/dm2 surface area in saline, 0.4 mg/dm2 from acrylic fibers in methanol, 3.6 mg/dm2 from polyester fibers in chloroform. Analysis showed only fiber polymer components and finish in saline and methanol leachates. Whilst further testing may be required for areas of special concern, since only a limited range of biological endpoints have been addressed, it is concluded that current and foreseeable future uses of these chemical fibers pose little or no toxicological hazard.

Acrylonitrile↗
PubMed1997

Evaluation of alternative methods for establishing safe levels of occupational exposure to vinyl halides.

The facts that reduction of occupational vinyl chloride exposures to levels within or below the 0.5-5 ppm range has so far been successful in eliminating vinyl chloride-induced liver angiosarcoma and that humans appear to be less sensitive to the carcinogenic effect of vinyl chloride than rats offered an opportunity to verify or dispute risk assessment extrapolation models used, and proposed, by the U.S. EPA. Safe occupational vinyl chloride exposures were defined as levels associated with an incidence of one angiosarcoma in 100,000 exposed workers, determined from rat bioassay data using default no-threshold (linearized multistage model and benchmark dose approach with linear extrapolation) and threshold (NOEL/LOEL and benchmark dose uncertainty factor approaches) models, and then compared against the likely protective range of 0.5-5 ppm. Safe levels derived using either no-threshold model are equivalent and are two to three orders of magnitude below the 0.5-5 ppm range. Safe levels derived using either threshold model, when applying uncertainty factors which reflect equal or less sensitivity in humans compared to rats, fall within the 0.5-5 ppm range. Similar results were obtained for vinyl bromide and vinyl fluoride. These results undermine the U.S. EPA default assumption of no-threshold for vinyl halides as well as for other DNA-reactive carcinogens while simultaneously supporting the notion that a practical threshold exists. They further suggest that when threshold models are appropriate, the default assumption of greater sensitivity in humans compared to rats should be carefully evaluated.

Animals↗
PubMed2000

Characterization of polyalkylvinyl ether phases by solid-state and suspended-state nuclear magnetic resonance investigations.

Pure organic polyalkvlvinyl ether phases were synthesized by suspension polymerization using different ratios and compositions of n-butylvinyl ether (C4VE) and n-octadecylvinyl ether (C18VE) with triethylene glycol divinyl ether or divinylbenzene as crosslinkers, respectively. These phases were investigated by means of solid-state 13C cross-polarization magic angle spinning nuclear magnetic resonance (NMR) spectroscopy and 1H high-resolution magic angle spinning (HR MAS) NMR spectroscopy in suspended-state. A comparison of these two methods showed the substantial advantages of 1H HR MAS NMR measurements. Structure elucidation was achieved using a 2D H,H-COSY NMR experiment performed under MAS conditions enabling full peak assignment of the 1H NMR spectra of these phases. The dynamic behavior of the polyalkylvinyl ether phases was determined by employing temperature-dependent measurements of spin-lattice relaxation times (T1) as well as accumulation of a 2D wide line separation NMR spectrum.

Magnetic Resonance Spectroscopy↗
PubMed1993

Cytotoxicity and DNA-protein crosslink formation in rat nasal tissues exposed to vinyl acetate are carboxylesterase-mediated.

Vinyl acetate is used in the paint, adhesive, and paper board industries. Vinyl acetate is a nasal carcinogen in rats exposed by inhalation for 2 years to 200 and 600 ppm, but not 50 ppm. Previous studies from our laboratory suggest that rat liver microsome-activated vinyl acetate induces plasmid DNA-histone crosslinks, in vitro, through esterase-mediated metabolism. Since nasal tissues contain high levels of carboxylesterase, tumorigenesis may be related to in situ production of the hydrolysis products acetaldehyde and acetic acid. Vinyl acetate was cytotoxic to both respiratory and olfactory tissues in vitro at 50-200 mM, but not 25 mM, after 2 hr exposure. Pretreatment of rats with the carboxylesterase inhibitor, bis-(p-nitrophenyl) phosphate (BNPP), attenuated the cytotoxic effects and metabolism of vinyl acetate in both tissue types. Semicarbazide, an aldehyde scavenger, was unable to protect the tissues from vinyl acetate-induced cytotoxicity. When the metabolites were tested, acetic acid, but not acetaldehyde, was cytotoxic to both tissues. The induction of DNA-protein crosslink (DPXL) formation by acetaldehyde and vinyl acetate in rat nasal epithelial tissues was detected using a sodium dodecyl sulfate/KCl precipitation technique. Endogenous crosslink levels ranged from 0.5 to 2.0% of total DNA and were considered background. Epithelial cells isolated from both olfactory and respiratory turbinates exhibited dose- and time-dependent increases in DPXL formation when exposed to 10-150 mM acetaldehyde for 1-2 hr at 37 degrees C. Similarly, respiratory and olfactory epithelial cells exposed to 5-75 mM vinyl acetate for 1-2 hr accumulated up to 12- and 15-fold higher crosslink levels than untreated cells, respectively. However, vinyl acetate appears to induce much higher levels of DPXLs at equimolar doses than acetaldehyde. This is thought to be related to stimulation of acetaldehyde-induced DPXL formation by the pH lowering effect of acetic acid production (via vinyl acetate hydrolysis). Pretreatment of the nasal turbinates with 1 mM BNPP reduced 25 mM vinyl acetate-induced DPXL formation by over 75% in both tissues. These data support a hypothesis that carboxylesterase-mediated hydrolysis of vinyl acetate is necessary to generate the active intracellular cross-linking agent, acetaldehyde, and the cytotoxic metabolite, acetic acid.

Acetaldehyde↗
PubMed1994

Reduced ability of rat preantral ovarian follicles to metabolize 4-vinyl-1-cyclohexene diepoxide in vitro.

4-Vinylcyclohexene diepoxide (1-epoxyethyl-3,4-epoxycyclohexane, VCD), an industrial chemical, is a potential health hazard because it destroys oocytes in small preantral follicles in rats. We proposed that VCD destroys oocytes in these follicles because of their reduced capacity to detoxify VCD (convert VCD to tetrol, 4-(1,2-dihydroxy)ethyl-1,2-dihydroxycyclohexane). Ovaries, livers, and adrenal glands were collected from immature and mature Fischer 344 rats. Tissues were dissociated and ovarian tissue was separated into distinct follicular fractions. Tissues were incubated with [14C]VCD and media were assayed for [14C]tetrol by HPLC. In immature rats, conversion of VCD to tetrol in large preantral follicles and hepatocytes was 1.5-fold greater than in small preantral follicles and 4-fold greater than in ovarian interstitial cells (p < 0.05). In adults, conversion of VCD to tetrol in large preantral follicles and hepatocytes was, respectively, 3- and 10-fold greater than in small preantral follicles and interstitial cells (p < 0.05). Compared with immature rats, all tissues from adult rats converted more VCD to tetrol (p < 0.05). These data demonstrate that interstitial cells and small preantral follicles from adult and immature rats have a reduced capacity to convert VCD to tetrol compared to large preantral follicles and liver cells. This may explain their increased susceptibility to VCD-induced ovotoxicity. Furthermore, adult rats may be less susceptible to VCD-induced ovotoxicity than immature rats.

Age Factors↗
PubMed1996

Involvement of apoptosis in 4-vinylcyclohexene diepoxide-induced ovotoxicity in rats.

Previous studies have determined that 4-vinylcyclohexene diepoxide (VCD) causes specific destruction of oocytes contained in small pre-antral (primordial and primary) ovarian follicles of Fischer 344 rats following 30 days of daily dosing with VCD. The purposes of this study were to identify the type of VCD-induced cell death occurring in small pre-antral follicles and to determine the earliest time following the onset of dosing when evidence of follicular destruction could first be detected. A significant decrease in the number of oocytes contained in small pre-antral follicles in ovaries of rats after 15 days of daily dosing (ip) with VCD (80 mg/kg) had been observed in preliminary experiments. Therefore, a study was conducted to determine the time of the onset of this follicular destruction by examination of follicular DNA integrity. Female Fischer 344 rats were dosed daily (80 mg/kg, i.p.) for 6, 8, 10, 12, or 14 days, and ovaries were removed 1, 4, or 24 hr after the final dose. Small pre-antral follicles (25-100 microns) were isolated by gentle dissociation of ovaries with collagenase, and follicles were sorted with micropipets. Genomic DNA was isolated from follicles and radiolabeled with [32P]dideoxy ATP, and the degree of fragmentation quantified by agarose gel electrophoresis and autoradiography. Degradation of DNA was evaluated by 32P content in low-molecular-weight fragments ( < 4 kilobase pairs). Degradation of DNA was not observed in follicles collected 24 hr after the final dose on any day. However, a random pattern of DNA degradation was observed, and was significantly greater (p < 0.05) compared with controls, when follicles were collected 4 hr following VCD administration on Days 10 and 12, but not on Days 6 or 8, of dosing. Although not significant, there was also evidence of DNA degradation in dosed animals on Day 14. Histological evaluation of small pre-antral follicles in ovarian sections during the early stages of VCD-induced DNA degradation (Day 10; 4 hr) demonstrated margination of chromatin along the nuclear membrane in oocytes and disruptions in focal contact between granulosa cells and oocytes, both features indicative of apoptosis. Furthermore, there was no sign of ruptured membranes in granulosa cells or oocytes or of an inflammatory response, characteristics of necrosis (pathological cell death). Whereas biochemical and morphological evidence of follicular destruction was seen 4 hr after dosing on Day 10, numbers of oocyte-containing primordial and primary follicles in VCD-treated animals were not different from controls at that time. These results demonstrate that the initial evidence of impending destruction of small pre-antral follicles is first consistently visualized following 10 days of daily dosing with VCD, although a measurable reduction in oocyte numbers has not yet occurred. Despite the fact that internucleosomal cleavage of genomic DNA was not observed, morphological evaluations support that granulosa cells and oocytes in primordial and primary follicles are destroyed via the induction of apoptosis.

Animals↗
PubMed1996

Enhanced expression of bax in small preantral follicles during 4-vinylcyclohexene diepoxide-induced ovotoxicity in the rat.

4-Vinylcyclohexene diepoxide (VCD) destroys small preantral (25-100 microns) ovarian follicles after repeated dosing in mice and rats. A previous study determined this follicular destruction is via apoptosis (physiological cell death). The purposes of this study were to examine the effects of VCD on amounts of mRNA for several genes that might be involved in this ovotoxic response and to determine the specificity of this response for small preantral follicles. The genes of interest were bax, a cell death gene; three forms of the antioxidant enzyme, superoxide dismutase (mitochondrial manganese-containing or MnSOD, cytosolic copper/zinc-containing or Cu/ZnSOD, and secreted or secSOD); and microsomal epoxide hydrolase (mEH), involved in detoxification of VCD. Female Fischer 344 rats were administered daily doses (10 days) of vehicle control (sesame oil) or VCD (80 mg/kg, ip). Four hours after the last injection, livers and ovaries were removed. Small (25-100 microns) and large (100-250 microns) preantral follicles were separated from the ovaries by gentle dissociation and collected by mouth pipeting. Total RNA was extracted from all tissues, reverse transcribed into first-strand cDNA, and amplified by polymerase chain reaction using oligonucleotide primers specific for each gene. Relative levels of mRNA were visualized by agarose gel electrophoresis and autoradiography and quantified by densitometric analysis. Coamplification of ribosomal protein L19 (constitutively expressed in ovarian tissue) was used for normalization in each sample. Increased levels of mRNA for bax (172 +/- 20% of control, p < 0.05), MnSOD (248 +/- 70% of control, p < 0.05), and mEH (352 +/- 120% of control, p < 0.05) were measured in 25- to 100-microns follicles collected from VCD-treated compared with control rats. Unlike 25- to 100-microns follicles (the targets of ovotoxicity), in 100- to 250-microns follicles (nontargets) there were no changes (p > 0.05) in mRNA levels for bax or MnSOD in VCD-treated rats; however, mRNA levels for mEH were significantly decreased (79 +/- 4% of control, p < 0.05), compared with control. No changes in levels of mRNA for mEH were observed in liver from VCD-treated rats relative to control. Additionally, in liver VCD caused a significant decrease in mRNA levels for bax (31 +/- 5% of control, p < 0.05) and Cu-ZnSOD (56 +/- 17% of control, p < 0.05). In summary, dosing of rats with VCD enhanced expression of mRNA encoding several genes that might respond during the induction of ovotoxicity. The selective increase in bax in the population of follicles destroyed by repeated dosing with VCD may reflect their susceptibility to apoptosis.

Animals↗
PubMed1997

Pharmacokinetics and metabolism of vinyl fluoride in vivo and in vitro.

Vinyl fluoride (VF) is an inhalation carcinogen at concentrations of 25 ppm or greater in rats and mice. The main neoplastic lesion induced in rodents was hepatic hemangiosarcomas, and mice were more sensitive than rats. In a first set of experiments, groups of three rats or five mice were exposed to VF in a closed-chamber gas uptake system at starting concentrations ranging from 50 to 250 ppm. Chamber concentrations of VF were measured every 10-12 min by gas chromatography. Partition coefficients were determined by the vial equilibration technique and used as parameters for a physiologically based pharmacokinetic (PBPK) model. Mice showed a higher whole-body metabolic capacity compared to rats (Vmax = 0.3 vs 0.1 mg/hr-kg). Both species had an estimated Km of < or = 0.02 mg/liter. The specificity for the oxidation of VF in vivo was determined by selective inhibition or induction of CYP 2E1. Inhibition with 4-methylpyrazole completely impaired VF uptake in rats and mice, whereas induction with ethanol (rats only) increased the metabolic capacity by two- to threefold. The pharmacokinetics of VF were also investigated in vitro. Microsomes from rat and mouse liver were incubated in a sealed vial with VF and an NADPH-regenerating system. Headspace concentrations (10-300 ppm) were monitored over time by gas chromatography. Consistent with the in vivo data, VF was metabolized faster by mouse microsomes than by rat microsomes (Vmax = 3.5 and 1.1 nmol/hr-mg protein, respectively). The rates of metabolism by human liver microsomes were generally in the same range as those found with rat liver microsomes (Vmax = 0.5-1.3 nmol/hr-mg protein), but one sample was similar to mice (Vmax = 3.3 nmol/ hr-mg protein). Metabolic rates in human microsomes were found to correlate with the amount of CYP 2E1 as determined by Western blotting and by chlorzoxazone 6-hydroxylation. It is concluded that the greater metabolic capacity of mice for VF both in vivo and in vitro may contribute to their greater susceptibility to tumor formation. CYP 2E1 is clearly the main isozyme involved in the oxidation of VF in all species tested. VF pharmacokinetics and metabolism in humans may depend upon the interindividual variability in the expression level of CYP 2E1. The excellent correspondence between in vivo and in vitro kinetics in rodents improves. substantially the degree of confidence for human in vivo predictions from in vitro data.

Administration, Inhalation↗
PubMed1997

Physiologically based modeling of vinyl acetate uptake, metabolism, and intracellular pH changes in the rat nasal cavity.

Chronic inhalation exposure to vinyl acetate (VA) causes lesions in the nasal cavity of the rat. This effect appears to be related to tissue exposure to either acetaldehyde (AAld) or acetic acid (AA) metabolites of VA or both. A physiologically based pharmacokinetic model was constructed to describe the deposition of VA in the nasal cavity of the rat and provide estimates of regional tissue exposure to VA, AAld, and AA. Since formation of AA in the nasal tissue should cause intracellular acidification, a submodel which describes free intracellular hydrogen ion concentration and intracellular pH (pHi) changes was linked to the VA model. The dosimetry model was applied to data from a series of experiments designed to measure the uptake and metabolism of VA in the isolated upper respiratory tract of the rat at exposure concentrations ranging from 73 to 2190 ppm. Extraction of VA from the nasal cavity was nonlinear with respect to exposure concentration and ranged from 36 to 94%, with the greatest deposition occurring at the lowest VA concentrations. Pretreatment with bis(p-nitrophenyl)phosphate, an inhibitor of carboxylesterases, significantly reduced fractional deposition of VA compared to naive rats exposed to similar VA concentrations. The best model fits for VA extraction and AAld appearance were achieved when a second carboxylesterase isozyme, with high-affinity characteristics, was included. Simulations of 6-h inhalation exposures to VA predicted that the order of nasal tissue exposures will be to AA > AAld > VA. In addition, based on measured tissue hydrolysis rates, sufficient acid should be formed by the metabolism of VA to cause significant changes in pHi. VA exposures of 200 and 600 ppm were predicted to result in a pHi of less than 7.2 and 6.7, respectively. This model provides nasal dosimetry estimates needed to develop mechanistically based risk assessment approaches for human exposures to VA vapor.

Acetaldehyde↗