Based on an analysis of mode of action, styrene-induced mouse lung tumors are not a human cancer concern.

Based on 13 chronic studies, styrene exposure causes lung tumors in mice, but no tumor increases in other organs in mice or rats. Extensive research into the mode of action demonstrates the key events and human relevance. Key events are: metabolism of styrene by CYP2F2 in mouse lung club cells to ring-oxidized metabolites; changes in gene expression for metabolism of lipids and lipoproteins, cell cycle and mitotic M-M/G1 phases; cytotoxicity and mitogenesis in club cells; and progression to preneoplastic/neoplastic lesions in lung. Although styrene-7,8-oxide (SO) is a common genotoxic styrene metabolite in in vitro studies, the data clearly demonstrate that SO is not the proximate toxicant and that styrene does not induce a genotoxic mode of action. Based on complete attenuation of styrene short-term and chronic toxicity in CYP2F2 knockout mice and similar attenuation in CYP2F1 (humanized) transgenic mice, limited metabolism of styrene in human lung by CYP2F1, 2 + orders of magnitude lower SO levels in human lung compared to mouse lung, and lack of styrene-related increase in lung cancer in humans, styrene does not present a risk of cancer to humans.

Modification of the metabolism and toxicity of styrene and styrene oxide in hepatic cytochrome P450 reductase deficient mice and CYP2F2 deficient mice.

Styrene causes toxicity in both the lung and the liver. The study of the relationship of this toxicity to the metabolism of styrene has been aided by the use of knockout mice for both bioactivation and detoxification pathways. It has been hypothesized that CYP2E1 is primarily responsible for styrene bioactivation in mouse liver and CYP2F2 in mouse lung. Two knockout strains were used in the current studies. Mice deficient in hepatic cytochrome P450 reductase had much less hepatic metabolism of styrene to styrene oxide. Styrene (600 mg/kg, i.p.) caused significant hepatotoxicity, as determined by serum sorbitol dehydrogenase and glutathione levels, in the wild-type but not in the knockout mice. It caused lung toxicity, as determined by protein levels, cell number, and lactate dehydrogenase activity in the bronchioalveolar lavage fluid of wild-type mice, but this effect was less in the knockout mice. In CYP2F2 knockout mice there was only a small decrease in the hepatic metabolism of styrene but a very large decrease in pulmonary metabolism. As expected the CYP2F2 knockout and wild-type mice were equally susceptible to styrene-induced hepatotoxicity, but the knockout mice were less susceptible to styrene-induced pneumotoxicity. Although the results are inconsistent with the simple hypothesis that styrene pneumotoxicity is due to the bioactivation of styrene to styrene oxide by CYYP2F2, they demonstrate the importance of both liver and lung in the metabolism of styrene, but additional pharmacokinetic studies are needed to help clarify the relationship between target organ metabolism and susceptibility.

The Toxicology Education Summit: building the future of toxicology through education.

Toxicology and careers in toxicology, as well as many other scientific disciplines, are undergoing rapid and dramatic changes as new discoveries, technologies, and hazards advance at a blinding rate. There are new and ever increasing demands on toxicologists to keep pace with expanding global economies, highly fluid policy debates, and increasingly complex global threats to public health. These demands must be met with new paradigms for multidisciplinary, technologically complex, and collaborative approaches that require advanced and continuing education in toxicology and associated disciplines. This requires paradigm shifts in educational programs that support recruitment, development, and training of the modern toxicologist, as well as continued education and retraining of the midcareer professional to keep pace and sustain careers in industry, government, and academia. The Society of Toxicology convened the Toxicology Educational Summit to discuss the state of toxicology education and to strategically address educational needs and the sustained advancement of toxicology as a profession. The Summit focused on core issues of: building for the future of toxicology through educational programs; defining education and training needs; developing the "Total Toxicologist"; continued training and retraining toxicologists to sustain their careers; and, finally, supporting toxicology education and professional development. This report summarizes the outcomes of the Summit, presents examples of successful programs that advance toxicology education, and concludes with strategies that will insure the future of toxicology through advanced educational initiatives.

Hepatotoxicity and pneumotoxicity of styrene and its metabolites in glutathione S-transferase-deficient mice.

Styrene is known to be hepatotoxic and pneumotoxic in rodents, and these adverse effects are related to its metabolism. Mice deficient in the enzymes responsible for both the activation and detoxification of styrene are useful in examining this relationship more closely. In the current study, mice deficient in glutathione S-transferase P1P2(-/-) (GST(-/-)) were compared with wild-type mice. Similar changes in serum sorbitol dehydrogenase, as an indicator of hepatotoxicity, and bronchioalveolar levels of protein, cells, and lactate dehydrogenase, as indicators of pneumotoxicity, were observed after styrene administration. Glutathione depletion followed a similar pattern. The administration of the toxic metabolite, styrene oxide, which is a direct substrate for glutathione metabolism, and 4-vinylphenol, which is a minor metabolite but is more potent than either styrene oxide, yielded results similar to those of styrene. The results indicate that either other isoforms of glutathione S-transferase are more important than the P1P2 form in styrene detoxification or that this pathway contributes in only a minor way to styrene detoxification, compared to other pathways.

Comparison of styrene oxide enantiomers for hepatotoxic and pneumotoxic effects in microsomal epoxide hydrolase-deficient mice.

Styrene is hepatotoxic and pneumotoxic in mice. Styrene oxide, the active metabolite, is detoxified via hydrolysis by microsomal epoxide hydrolase (mEH). Racemic styrene oxide was previously found to be more lethal and produced increased toxicity in mEH-/- mice compared to wild-type mice. The hepatotoxicity and pneumotoxicity of the R- and S-styrene oxide (SO) enantiomers were compared in wild-type and mEH-deficient mice (mEH-/-). Twenty-four hours following administration of 150 mg/kg ip, neither enantiomer produced hepatotoxicity, but S-SO was more pneumotoxic. However, in mEH-/- mice R-SO produced greater decreases in hepatic glutathione levels 3 h after administration. The basis for the unusual greater toxicity of S-SO, rather than the generally more toxic R-SO, in mEH-/- mice may be related to differences in detoxification by EH.

Metabolism and toxicity of styrene in microsomal epoxide hydrolase-deficient mice.

Styrene, which is widely used in manufacturing, is both acutely and chronically toxic to mice. Styrene is metabolized by cytochromes P-450 to the toxic metabolite styrene oxide, which is detoxified via hydrolysis with microsomal epoxide hydrolase (mEH) playing a major role. The purpose of these studies was to characterize the importance of this pathway by determining the hepatotoxicity and pneumotoxicity of styrene in wild-type and mEH-deficient (mEH(-/-)) mice. While the mEH(-/-) mice metabolized styrene to styrene oxide at the same rate as the wild-type mice, as expected there was minimal metabolism of styrene oxide to glycol. mEH(-/-) mice were more susceptible to the lethal effects of styrene. Twenty-four hours following the administration of 200 mg/kg ip styrene, mice demonstrated a greater hepatotoxic response due to styrene, as measured by increased serum sorbitol dehydrogenase activity and greater pneumotoxicity as shown by increased protein levels, cell numbers, and lactate dehydrogenase activity in bronchioalveolar lavage fluid. mEH(-/-) mice were also more susceptible to styrene-induced oxidative stress, as indicated by greater decreases in hepatic glutathione levels 3 h after styrene. Styrene oxide at a dose of 150 mg/kg did not produce hepatotoxicity in either wild-type or mEH(-/-) mice. However, styrene oxide produced pneumotoxicity that was similar in the two strains. Thus, mEH plays an important role in the detoxification of styrene but not for exogenously administered styrene oxide.

Depletion by styrene of glutathione in plasma and bronchioalveolar lavage fluid of non-Swiss albino (NSA) mice.

Styrene is a widely used chemical, but it is known to produce lung and liver damage in mice. This may be related to oxidative stress associated with the decrease in the levels of reduced glutathione (GSH) in the target tissues. The purpose of this study was to investigate the effect of styrene and its primary metabolites R-styrene oxide (R-SO) and S-styrene oxide (S-SO) on GSH levels in the lung lumen, as determined by amounts of GSH in bronchioalveolar lavage fluid (BALF) and in plasma. When non-Swiss albino (NSA) mice were administered styrene (600 mg/kg, ip), there was a significant fall in GSH levels in both BALF and plasma within 3 h. These returned to control levels by 12 h. The active metabolite R-SO (300 mg/kg, ip) also produced significant decreases in GSH in both BALF and plasma, but S-SO was without marked effect. Since GSH is a principal antioxidant in the lung epithelial lining fluid, this fall due to styrene may exert a significant influence on the ability of the lung to buffer oxidative damage.

Indicators of oxidative stress and apoptosis in mouse whole lung and Clara cells following exposure to styrene and its metabolites.

In mice, styrene is hepatotoxic, pneumotoxic, and causes lung tumors. One explanation for the mechanism of toxicity is oxidative stress/damage. Previous studies have shown decreased glutathione levels, linked to increased apoptosis, in lung homogenates and isolated Clara cells 3 h following styrene or styrene oxide (SO) administration or in vitro exposure. The objective of the current studies was to determine what effects styrene and its active metabolites, primarily styrene oxide, had on indicators of oxidative stress and attendant apoptosis in order to understand better the mechanism of styrene-induced toxicity. Three hours following in vitro exposure of Clara cells to styrene or SO there were increases in reactive oxygen species (ROS). Following administration of styrene or styrene oxide ip, increases in ROS, superoxide dismutase (SOD), and 8-hydroxydeoxyguanosine (8-OHdG) formation were observed. Since increases in ROS have been linked to increases in apoptosis ratios of bax/bcl-2, mRNA and protein expression were determined 3-240 h following the administration of styrene and R-styrene oxide (RSO). The bax/bcl-2 mRNA ratio increased 12 and 24 h following R-SO and 120 h following styrene administration. However, the bax/bcl-2 protein ratio was not increased until 240 h following R-SO, and 24 and 240 h following styrene administration. However, only a slight increase in caspase 3 was observed. These results indicated that oxidative stress occurred 3h following styrene or styrene oxide as evidenced by increased ROS and SOD. This increased ROS may be responsible for the increased 8-OHdG formation. Our findings of limited apoptosis in Clara cells following acute exposure to styrene or SO are in agreement with others and may reflect the minimal extent to which apoptosis plays a role in acute styrene toxicity. It is clear, however, that oxidative stress and oxidative effects on DNA are increased following exposure to styrene or styrene oxide, and these may play a role in the lung tumorigenesis in mice.

Effect of multiple doses of styrene and R-styrene oxide on CC10, bax, and bcl-2 expression in isolated Clara cells of CD-1 mice.

Styrene exposure is highest among workers in the reinforced plastics industry with exposure seen for 5 consecutive days during the work week. Styrene is both hepatotoxic and pneumotoxic in mice, in addition to causing lung tumors. Human epidemiological studies are inconclusive as to the carcinogenicity of styrene so it is important to understand the mechanism responsible for styrene tumors in mice. Previous studies showed significant decreases in CC10 protein for 5 days following a single dose of the active metabolite R-styrene oxide (R-SO), yet little change in the bax/bcl-2 protein ratio was seen until 10 days following styrene or R-SO administration. Styrene or R-SO was given to CD-1 mice for 5 consecutive days. Mice were euthanized 24h, 10 days or 30 days following the last dose, and CC10, bax and bcl-2 mRNA and protein levels were determined in isolated Clara cells. CC10 mRNA levels were decreased at 24h for both styrene and R-SO. R-SO decreased CC10 protein levels up to 10 days following the last dose. Increases in the bax/bcl-2 mRNA and protein ratio were seen 24h following R-SO administration. Styrene did not significantly increase the bax/bcl-2 mRNA ratio until 10 days after treatment, with the bax/bcl-2 protein ratio increased at both 10 days and 30 days. It is likely that oxidative stress is involved in the toxicity caused by styrene and that minimal apoptosis may be involved. Chronically decreased CC10 levels may lead to increases in oxidative stress in Clara cells, the main target for styrene toxicity in the lung, and may be an early indicator for lung carcinogenesis in mice.

Oxidative stress due to (R)-styrene oxide exposure and the role of antioxidants in non-Swiss albino (NSA) mice.

Styrene produces lung and liver damage that may be related to oxidative stress. The purpose of this study was to investigate the toxicity of (R)-styrene oxide (R-SO), the more active enantiomeric metabolite of styrene, and the protective properties of the antioxidants glutathione (GSH), N-acetylcysteine (NAC), and 4-methoxy-L-tyrosinyl-gamma-L-glutamyl-L-cysteinyl-glycine (UPF1) against R-SO-induced toxicity in non-Swiss Albino (NSA) mice. UPF1 is a synthetic GSH analog that was shown to have 60 times the ability to scavenge reactive oxygen species (ROS) in comparison to GSH. R-SO toxicity to the lung was measured by elevations in the activity of lactate dehydrogenase (LDH), protein concentration, and number of cells in bronchoalveolar lavage fluid (BALF). Toxicity to the liver was measured by increases in serum sorbitol dehydrogenase (SDH) activity. Antioxidants were not able to decrease the adverse effects of R-SO on lung. However, NAC (200 mg/kg) ip and GSH (600 mg/kg), administered orally prior to R-SO (300 mg/kg) ip, showed significant protection against liver toxicity as measured by SDH activity. Unexpectedly, a synthetic GSH analog, UPF1 (0.8 mg/kg), administered intravenously (iv) prior to R-SO, produced a synergistic effect with regard to liver and lung toxicity. Treatment with UPF1 (0.8 mg/kg) iv every other day for 1 wk for preconditioning prior to R-SO ip did not result in any protection against liver and lung toxicity, but rather enhanced the toxicity when administered prior R-SO. The results of the present study demonstrated protection against R-SO toxicity in liver but not lung by the administration of the antioxidants NAC and GSH.

Application of the sodium dilution principle to calculate extracellular fluid volume changes in horses during dehydration and rehydration.

OBJECTIVE: To apply the principle of sodium dilution to calculate the changes in the extracellular fluid (ECF) volume (ECFV) and intracellular fluid volume (ICFV) that occur during dehydration and rehydration in horses. ANIMALS: 8 healthy horses of various breeds. PROCEDURES: Horses were dehydrated over 4 hours by withholding water and administering furosemide. Saline (0.9% NaCl) solution was administered IV during the next 2 hours (20 mL/kg/h; total 40 mL/kg). Horses were monitored for an additional hour following IV fluid administration. Initial ECFV was determined by use of multifrequency bioelectrical impedance analysis, and serum sodium concentration was used to calculate total ECF sodium content. Sodium and fluid volume losses were monitored and calculated throughout the study and used to estimate changes in ECFV and ICFV during fluid balance alterations. RESULTS: Changes during dehydration and rehydration primarily occurred in the ECFV. The sodium dilution principle estimated an overexpansion of the ECFV beyond the volume of fluid administered, indicating a small contraction of the ICFV in response to fluid administration. Serum and urinary electrolyte changes were recorded and were consistent with those of previous reports. CONCLUSIONS AND CLINICAL RELEVANCE: The sodium dilution principle provided a simple method that can be used to estimate the changes in ECFV and ICFV that occur during fluid administration. Results suggested an overexpansion of the ECFV in response to IV saline solution administration. The sodium dilution principle requires further validation in healthy and clinically ill horses, which could provide clinical applications similar to those in other species.

CC10 mRNA and protein expression in Clara cells of CD-1 mice following exposure to styrene or its metabolites styrene oxide or 4-vinylphenol.

Styrene, widely used in manufacturing, has both acute and chronic effects in humans. In mice, styrene is both hepato- and pneumo-toxic and causes lung tumors. The primary site for styrene metabolism and its effects in mouse lung is the Clara cell, which secretes Clara cell 10kDa protein (CC10) and surfactant protein A (SPA). Both play important roles in host defenses and inflammation prevention. The mode of action for styrene-induced lung tumor formation has yet to be elicited, yet one possibility relates to oxidative stress and decreased CC10 levels. CC10 mRNA and protein expression were measured in isolated Clara cells 3, 12, and 24h following in vivo administration of styrene (600mg/kg i.p.) or its metabolites [R-, S-, racemic styrene oxide (SO) (300mg/kg i.p.), 4-vinylphenol (100mg/kg i.p.)]. The largest decreases in CC10 mRNA expression were seen with R-SO and racemic SO at 24h. To determine if rebound effects would be seen, CC10 mRNA and protein expression were determined 48, 120, and 240h following styrene and R-SO administration. The CC10 protein level did not reach its lowest point to correlate with mRNA expression until 120h after R-SO administration. Styrene exposure caused a significant decrease in CC10 protein after 24h, rebounding through 240h. SPA protein expression showed little change from control levels, indicating a more specific effect on CC10 in the Clara cell by styrene and its metabolites. These studies demonstrate that acute changes in lung CC10 protein and mRNA expression do occur following in vivo treatment with styrene and its metabolites. These changes may be early indicators for a potential mechanism for lung tumor formation in mice as it relates to oxidative stress and the possibility deserves further study.

Critical appraisal of the expression of cytochrome P450 enzymes in human lung and evaluation of the possibility that such expression provides evidence of potential styrene tumorigenicity in humans.

Styrene is widely used with significant human exposure, particularly in the reinforced plastics industry. In mice it is both hepatotoxic and pneumotoxic, and this toxicity is generally thought to be associated with its metabolism to styrene oxide. Styrene causes lung tumors in mice but not in rats. The question is how the tumorigenic effect in mouse lung may relate to the human. This review examines the comparison of the metabolic activation rates (1) between the liver and lung and (2) for the lung, between the rodent and human. Emphasis is placed on the specific cytochromes P450 present in the lungs of humans and what role they might play in the bioactivation of styrene and other compounds. In general, pulmonary metabolism is very slow compared to hepatic metabolism. Furthermore, metabolic rates in humans are slow compared to those in rats and mice. There is a wide difference in what specific cytochromes P450 investigators have reported as being present in human lung which makes comparisons, both inter-species and inter-organ, difficult. The general low activity for cytochrome P450 activity in the lung, especially for CYP2F1, the human homolog for CYP2F2 which has been identified in mice as being primarily responsible for styrene metabolism, argues against the hypothesis that human lung would produce enough styrene oxide to damage pulmonary epithelial cells leading to cell death, increased cell replication and ultimately tumorigenicity, the presumed mode of action for styrene in the production of the mouse lung tumors.

Estimation of acute fluid shifts using bioelectrical impedance analysis in horses.

BACKGROUND: Multi-frequency bioelectrical impedance analysis (MF-BIA) has been used to evaluate extracellular fluid volume (ECFV), but not fluid fluxes associated with fluid or furosemide administration in horses. If able to detect acute changes in ECFV, MF-BIA would be useful in monitoring fluid therapy in horses. HYPOTHESIS: The purpose of this study was to evaluate the ability of MF-BIA to detect acute fluid compartment changes in horses. We hypothesized that MF-BIA would detect clinically relevant (10-20%) changes in ECFV. ANIMALS: Six healthy mares were used in the study. METHODS: This is an original experimental study. Mares were studied in 3 experiments: (1) crystalloid expansion of normally hydrated subjects, (2) furosemide-induced dehydration followed by crystalloid administration, and (3) acute blood loss followed by readministration of lost blood. MF-BIA measurements were made before, during, and after each fluid shift and compared to known changes in volume calculated based on the intravenous fluids that were administered in addition to urinary fluid losses. Mean errors between MF-BIA estimated change and known volume change were compared using nonparametric analysis of variance. Estimated ECFV pre- and post-fluid administration similarly were compared. The level of statistical significance was set at P < .05. RESULTS: Results of the study revealed a statistically significant change in ECFV and total body water during crystalloid expansion and dehydration. Statistically significant changes were not observed during blood loss and administration. Mean errors between MF-BIA results and measured net changes were small. CONCLUSIONS AND CLINICAL IMPORTANCE: MF-BIA represents a practical and accurate means of assessing acute fluid changes during dehydration and expansion of ECFV using isotonic crystalloids with potential clinical applications in equine critical care.

Comparison of styrene and its metabolites styrene oxide and 4-vinylphenol on cytotoxicity and glutathione depletion in Clara cells of mice and rats.

Styrene is a widely used compound in the manufacturing industry. In mice and rats, it is both hepatotoxic and pneumotoxic. It causes lung tumors in mice, but not in rats. The Clara cell is the main target for the toxicity of styrene and its metabolites, and it also has the greatest activity for styrene metabolism. Therefore, Clara cells isolated from CD-1 mice and Sprague-Dawley rats were used to compare the cytotoxicities induced by styrene and its metabolites. The cytotoxicity of styrene was greater in vitro than that of its metabolites styrene oxide (racemic, R- and S-) and 4-vinylphenol in contrast with what has been observed in vivo in previous studies on hepatotoxicity and pneumotoxicity. Susceptibility of rats to styrene and its metabolites are 4-fold less than that observed with mice. Glutathione levels were also measured in mice following addition of the chemicals in vitro and treatment of the CD-1 mice in vivo. Decreases in glutathione concentrations were seen even at doses which did not cause the death of mouse Clara cells. Significant decreases in glutathione were observed 3h after treatment with racemic SO and R-SO. At 12h, rebound effects were seen for all compounds, with all but R-SO rebounding above controls. These studies suggest that in vitro cytotoxicity of styrene and its metabolites does not strictly follow in vivo effects and that decreases in mouse glutathione levels may be related to oxidative stress.

Effects of styrene and styrene oxide on glutathione-related antioxidant enzymes.

Styrene is both hepatotoxic and pneumotoxic in mice. Its mode of action is not clear, but it may be related to oxidative stress including a very large decrease in reduced glutathione (GSH). The current studies evaluated if: (1) the more toxic R-styrene oxide had a greater effect on reduced GSH levels than the less toxic S-styrene oxide, (2) the ratio of reduced to oxidized forms of glutathione was altered by styrene or styrene oxide, (3) other enzymes involved in the oxidant status of the cell, namely glutathione reductase, glutathione peroxidase and gamma-glutamylcysteine synthetase were altered, and (4) lipid peroxidation, as measured by the determination of malondialdehyde, increased. R-Styrene oxide (300mg/kg, ip) caused greater decreases in mouse liver and lung GSH than did S-styrene oxide (300mg/kg, ip). Styrene (600mg/kg, ip) caused decreases in both GSH and GSSG in both liver and lung. Styrene and styrene oxide did not cause significant increases in lipid peroxidation in either liver or lung. Styrene and styrene oxide had minimal effects on glutathione reductase and glutathione peroxidase in liver and lung. Styrene increased gamma-glutamylcysteine synthetase activity. The results suggest that while styrene and its metabolite styrene oxide cause significant decreases in GSH levels, they have little effect on the enzymes glutathione reductase and glutathione peroxidase and that in response to decreased glutathione levels there is an increase in its synthesis via induction of gamma-glutamylcysteine synthetase activity.

Bioavailability of 2,3',4,4',5-pentachlorobiphenyl (PCB118) and 2,2',5,5'-tetrachlorobiphenyl (PCB52) from soils using a rat model and a physiologically based extraction test.

The bioavailability of coplanar 2,3',4,4',5-pentachlorobiphenyl (PCB118) and nonplanar 2,2',5,5'-tetrachlorobiphenyl (PCB52) from soils representing a range in organic carbon (OC), clay content and pH were investigated using an in vivo rat model and an in vitro physiologically based extraction test (PBET) to assess the role of soil and chemical properties on bioavailabilty. Affinity to soil and persistence of PCBs have been shown to increase with increasing soil organic carbon (OC) content, PCB chlorination, and PCB coplanarity. In the in vivo tests for both PCB118 and PCB52, the AUCs following iv injection were significantly higher than the AUCs for all soil groups, indicating that the soil matrix can reduce the absolute bioavailability of PCB118 and PCB52. However, no significant differences were detected between soils of different properties. In the in vitro PBET, significant differences in the mobilization of PCB118 and PCB52 were observed among soils, and PCBs had the least mobilization from the soil with the highest OC content consistent with hydrophobic partitioning theory. Also, significantly less PCB118 was mobilized relative to PCB52 in the PBET assay, showing the potential impact of spatial orientation and chlorine content on bioavailability. No correlation between the in vitro PBET and the in vivo rat model was observed for the PCBs. Although the in vitro PBET and related assays may serve as an indicator of bioavailability, it is likely to underestimate what can be released from a soil in an in vivo assay.

Ring-oxidized metabolites of styrene contribute to styrene-induced Clara-cell toxicity in mice.

Styrene produced cytotoxicity in the terminal bronchioles of mice, but not rats, due to metabolites produced in situ by CYP2F2 metabolism. It has generally been presumed that styrene toxicity is mediated by styrene 7,8-oxide, but styrene oxide is not much more toxic than styrene. In contrast, ring-oxidized metabolites (4-vinylphenol or its metabolites) induce much greater toxicity. Administration of 4-vinylphenol results in pneumotoxicity, based on analysis of bronchoalveolar lavage fluid (BALF) at a 5- to 10 fold lower dose than does styrene oxide. In the current research, studies demonstrated that ip administration of 4-vinylphenol for 14 consecutive days at dosages of 6, 20, or 60 mg/kg/d (split into 3 doses) produced cytotoxicity in the terminal bronchioles of mice, but not rats. While higher doses of 4-vinylphenol produced adverse effects in both liver and lung, no liver toxicity was seen in mice exposed to 60 mg/kg/d for 14 d. Approximately 4 d was required for BALF parameters to return to normal following a single administration of 4-vinylphenol. These studies add further support for the role of ring-oxidized metabolites in the pneumotoxicity induced by styrene in mice and the lack thereof in rats.

Serum hepatitis associated with commercial plasma transfusion in horses.

This report describes 4 fatal cases of serum hepatitis associated with the administration of commercial plasma in the horse. Serum hepatitis in the horse is characterized by acute hepatic central lobular necrosis, and it has been associated with the administration of biological products of equine origin. None of these horses had a recent history of equine biologic-origin vaccination; however, they had received 1.5-5 L of commercial plasma, and in I horse, an additional 8 L of fresh blood. Acute, severe colic unresponsive to medical therapy, lethargy, or sudden death developed in these 4 horses 41 to 60 days later. Two of the horses developed encephalopathy, confirmed in 1 horse by the presence of severe diffuse Alzheimer type II astrocytes in the brain. Although the prevalence of serum hepatitis associated with the administration of commercial plasma appears to be low in the horse, it should be considered an uncommon but potentially fatal risk factor.