Abstract  Samples of mother's milk were collected from Bayonne, NJ; Jersey City, NJ; Pittsburgh, PA; Baton Rouge, LA; and Charleston, WV, and analyzed for volatile (purgeables) and semivolatile (extractable) organics using glass capillary gas chromatography/mass spectrometry/computer. In the volatile fraction, 26 halogenated hydrocarbons, 17 aldehydes, 20 ketones, 11 alcohols, 2 acids, 3 ethers, 1 epoxide, 14 furans, 26 other oxygenated compounds, 4 sulfur-containing compounds, 7 nitrogen-containing compounds, 13 alkanes, 12 alkenes, 7 alkynes, 11 cyclic hydrocarbons, and 15 aromatics were found, including major peaks for hexanal, limonene, dichlorobenzene, and some esters. The levels of dichlorobenzene appeared to be significantly higher in the samples from Jersey City and Bayonne than in samples from other sites. Jersey City samples also appeared to have significantly higher levels of tetrachloroethylene. Charleston and Jersey City samples appeared to have significantly higher levels of chloroform; however, chloroform was observed in the blanks at about 20% of that in the samples. Due to the small sample size and lack of control over the solicitation of sample donors, the data cannot be used to extrapolate to the general population. Fewer semivolatile compounds of interest were found. Polychlorinated naphthalenes, polybrominated biphenyls, chlorinated phenols, and other compounds were specifically sought and not detected (limit of detection about 20-100 ng/mL milk). Polychlorinated biphenyls (PCBs) and DDE were found.

Abstract  The mechanisms responsible for ethanol-mediated teratogenesis have not been resolved. However, possible etiologies include the local formation of the teratogen acetaldehyde or oxygen radicals by fetal ethanol-oxidizing enzymes. As alcohol dehydrogenases are expressed at very low concentrations in human embryonic tissues, the ethanol-inducible P450 enzyme, CYP2E1, could be the sole catalyst of fetal ethanol oxidation. With this in mind, we examined the expression of this P450 in liver samples from fetuses ranging in gestational age from 16 to 24 weeks. Immunoblot analysis of fetal liver microsomes revealed the presence of a protein immunoreactive with CYP2E1 antibodies that exhibited a slightly lower molecular weight than that found in adult liver samples. Embryonic CYP2E1 expression was further confirmed by the reverse transcriptase reaction with RNA from a 19-week gestational fetal liver used as template. Catalytic capabilities of human fetal microsomes were assessed by measurement of the rate of ethanol oxidation to acetaldehyde, which were 12-27% of those exhibited by adult liver microsomes. Immunoinhibition studies with CYP2E1 antibodies revealed that the corresponding antigen was the major catalyst of this reaction in both fetal and adult tissues. We then assessed whether embryonic CYP2E1 was, like the adult enzyme, inducible by xenobiotics. Treatment of primary fetal hepatocyte cultures with either ethanol or clofibrate demonstrated a 2-fold increase in CYP2E1 levels compared with untreated cells. Collectively, our results indicate that CYP2E1 is present in human fetal liver, that the enzyme is functionally similar to CYP2E1 from adults, and that fetal hepatocyte CYP2E1 is inducible in culture by xenobiotics, including ethanol. Because fetal CYP2E1 mediates ethanol metabolism, the enzyme may play a pivotal role in the local production of acetaldehyde and free radicals, both of which have potential deleterious effects on the developing fetus.

Abstract  SUMMARY: Fatty liver disease is common in Western countries. Some patients with this condition develop steatohepatitis, with ongoing liver injury that can lead to cirrhosis. Liver biopsy is currently required to differentiate between uncomplicated fatty liver disease and the more serious condition of steatohepatitis. Salameh and colleagues (1) studied the potential role of MR elastography for this diagnostic task in rat models of simple fatty liver and steatohepatitis. Their results suggest that MR elastography may have a potentially important role for noninvasive early detection of steatohepatitis in patients with fatty liver disease.

Abstract  The document presents a compilation of measured values for physiological parameters used in pharmacokinetic modeling. The physiological parameters include body weight, tissue volumes, cardiac output distribution, and respiration parameters. Reference values for use in risk assessment are given for each of the physiological parameters based on analyses of valid measurements obtained from the literature and other reliable sources. The proposed reference values are for generic mice and rats without regard to sex or strain. Reference values for humans are without regard to age or sex. Differences between the sexes in mice, rats, and humans are accounted for by scaling the reference parameters within species on the basis of body weight. Reference physiological parameters are for a 0.025 kg mouse, 0.25 kg rat, and a 70 kg man.

Abstract  Simultaneous administration of trichloroethylene (TCE), at an oral dose of 0.5 ml/kg, resulted in a marked potentiation of liver injury caused by an oral dose of carbon tetrachloride (CCl4, 0.05 ml/kg). Hepatic glutathione levels were depressed at 24 hr only in the rats given TCE and CCl4. Using serum enzyme (ALT and SDH) as indicators of hepatotoxicity, potentiation of CCl4-injury was most apparent at 24 hr. Upon histological examination of H&E stained liver sections, the differences between livers obtained from TCE and CCl4-treated rats versus CCl4-treated rats were most apparent at later time points (48 and 72 hr). At 48 hr after CCl4, livers showed a distinctive and uniform pattern of injury with regeneration features predominating over necrosis. At this time, livers from TCE and CCl4-treated rats were characterized by extensive zone 3 coagulative necrosis. Inflammatory infiltrations were less prominent. At 72 hr, morphological features of livers from TCE and CCl4 rats were similar to those from rats given CCl4 alone at 48 hr. From the results obtained, it appears that the regenerative activity of the liver may be delayed in rats simultaneously administered TCE and CCl4 as compared to rats administered only CCl4.

Abstract  The public depends on competent risk assessment from the federal government and the scientific community to grapple with the threat of pollution. When risk reports turn out to be overblown--or when risks are overlooked--public skepticism abounds. This comprehensive and readable book explores how the U.S. Environmental Protection Agency (EPA) can improve its risk assessment practices, with a focus on implementation of the 1990 Clean Air Act Amendments. With a wealth of detailed information, pertinent examples, and revealing analysis, the volume explores the "default option" and other basic concepts. It offers two views of EPA operations: The first examines how EPA currently assesses exposure to hazardous air pollutants, evaluates the toxicity of a substance, and characterizes the risk to the public. The second, more holistic, view explores how EPA can improve in several critical areas of risk assessment by focusing on cross-cutting themes and incorporating more scientific judgment. This comprehensive volume will be important to the EPA and other agencies, risk managers, environmental advocates, scientists, faculty, students, and concerned individuals.

Abstract  Neurophysiologic, neurobehavioral, and neuropsychologic profiles in 17 grain storage workers, 1 grain inspector, and 4 malting laboratory workers are described. The effects of CS2 toxicity as seen in viscose rayon workers as well as in experimental animals is remarkably similar to the clinical profile of our grain storage workers. CS2 use explains the dysfunction of peripheral axons, auditory nerve, the optic nerve, and the extrapyramidal system, as well as altered behavior and cognition changes. The signs and symptoms in these workers seem to be dose-related and we note that workers separated out from the areas where fumigation took place reported improvement not seen by fellow workers who continued the fumigant treatment routine. Likewise, malting laboratory workers exposed only to the grain dust from 3 to 7 years showed only minimal symptoms. Though a number of mechanism have been suggested for the alteration of neuropsychological function, the chelating ability of DDC derived from CS2 and its ability to markedly increase copper and zinc within the central nervous system suggests a mechanism of toxicity analogous to copper intoxication as in Wilson's Disease and may explain the production of extrapyramidal symptoms in these patients. Chelation of copper might prove therapeutic in CS2 poisoning. It is obvious that both basic and clinical research will be necessary to sort out the questions raised. We applaud the EPA's decision to ban the use of 80/20 fumigants and also methyl bromide, and trust that similar toxic substances be carefully studied before their selection for replacing these previous toxic agents. We further decry the technique of re-introducing grain dust into the food chain rather than destroying it, since the dust contains very high residues of fumigant material. We speculate on the possible role of CS2 and other pesticides in the food chain and the incidence of Parkinsonian symptoms in these patients and the general public.

Abstract  A physiologically based pharmacokinetic model which describes the behavior of inhaled styrene in rats accurately predicts the behavior of in baled styrene in humans. The model consists of a series of mass-balance differential equations which quantify the time course of styrene concentration within four tissue groups representing (1) highly perfused organs, (2) moderately perfused tissues such as muscle. (3) slowly perfused fat tissue, and (4) organs with high capacity to metabolize styrene (principally liver). The pulmonary compartment of the model incorporates uptake of styrene controlled by ventilation and perfusion rates and the blood:air partition coefficient The metabolizing tissue group incorporates saturable Michaelis-Menten metabolism controlled by the biochemical constants Vmax and Km. With a single set of physiological and biochemical constants, the model adequately simulates styrene concentrations in blood and fat of rats exposed to 80, 200, 600, or 1200 ppm styrene (data from previously published studies). The simulated behavior of styrene is particularly sensitive to changes in the constants describing the fat tissue group, and to the maximum metabolic rate described by Vmax, The constants used to simulate the fate of stvrene in rats were scaled up to represent humans. Simulated styrene concentrations in blood and exhaled air of humans are in good agreement with previously published data. Model simulations show that styrene metabolism is saturated at inhaled concentrations above approximately 200 ppm in mice, rats, and humans. At inhaled concentrations below 200 ppm, the ratio of styrene concentration in blood to inhaled air is controlled by perfusion limited metabolism. At inhaled concentrations above 200 ppm. This ratio is controlled by the blood:air partition coefficient and is not linearly related to the ratio attained at lower (nonsaturating) exposure concentrations. These results show that physiologically based pharmacokinetic models provide a rational basis with which (1) to explain the relationship between blood concentration and air concentration of an inhaled chemical, and (2) to extrapolate this relationship from experimental animals to humans.

Abstract  Partition coefficients are required for developing physiologically based pharmacokinetic models used to assess the uptake, distribution, tabolism, and elimination of volatile chemicals in mammals. A gas-phase vial equilibration technique is presented for determining the liquid:air and tissue:air partition coefficients for low-molecular-weight volatile chemicals. This technique was developed from two previously described medium:air methods, relied solely on measurement of chemical concentration in the gas phase, and, compared to earlier work, extends the range of chemicals and tissues examined. Partition coefficients were determined with 0.9% saline, olive oil, and blood, liver, muscle, and fat tissues from rats for 55 compounds. Human blood:air coefficients were determined for 36 compounds and several blood:air values were also determined in the mouse and for one compound in the hamster. An approach is described for predicting the tissue solubilities of untested compounds based on oil:air and saline:air coefficients using regression analyses. A similar approach is used to model fat:air coefficients in terms of oil:air values and to model human blood: air coefficients in terms of rat blood:air coefficients.

Abstract  The percutaneous absorption of 8 chlorinated solvents were studied. The ex-perimental method consisted of the application of the solvent to the abdominal mouse skin and quantitating its absorption through the skin by its presence in whole body and its appearance in expiration. Determination of the solvent in tissues and expiration was carried out by gas chromatographic methods. There was a great diversity of ability among solvents to penetrate the mouse skin. Dichloromethane was absorbed to an amount which was 53 times as large as the amount of tetrachloroethyene. Among tested solvents, those which had the highest solubility in water showed the greatest absorption rate, while those having the lowest solubility in water gave the smallest absorption rate from skin. The linear relationship between the absorption rate from skin and the solubility in water was found: in case of X ?? 16, Y=30.8+2.13X, r=0.87; in case of X ?? 16, Y= -52.8+6.59X, r=1.00; where Y is the percutaneous absorption rate (nM/min/cm2 of skin) and X is the solubility in water of solvent (mM at 25°C).

Abstract  Forty-six coded chemicals were tested for their ability to induce sister chromatid exchanges (SCEs) and chromosomal aberrations (ABs) in cultured Chinese hamster ovary (CHO) cells using a standard protocol with and without exogenous metabolic activation. Sixteen chemicals were negative and 15 were positive in both assays; 15 were positive for SCEs only (one chemical that was positive for SCEs was equivocal for ABs), and no chemicals induced ABs only. The effect of cell harvest time on the ability to detect the induction of ABs was examined for 18 chemicals. Seven chemicals produced a positive response using both standard and extended harvest times, five were positive only using an extended harvest time, and six were negative using both harvest times. The relationship between cell cycle delay and SCE induction was also examined, and the two appear to be unrelated.

Abstract  Effect-air concentration regressions of 48 common solvents (aromatic, aliphatic, and chlorinated hydrocarbons, alcohols, ketones, acetates) were determined for 4-hr inhalation exposures in male rats and for 2-hr exposures in female mice. Inhibition of propagation and maintenance of the electrically evoked seizure discharge was used as a criterion of the acute neurotropic effect. The isoeffective concentrations in air were estimated by interpolation on the level of one-third of the maximum effect (ECC). ECC estimates ranged from 90 to 24,000 ppm and were several times lower than concentrations evoking behavioral inhibition and by one to two orders lower than concentrations inducing narcosis. Correlations between corresponding values in both species were high (r > 0.9), indicating a relative independence of the estimates from experimental conditions. The relative potency estimates had only negligible correlation with octanol:water distribution coefficients or other physicochemical predictors for the whole sample of solvents, but moderate to high correlation (r = 0.5 to 0.9) in homogenous groups of nonpolar solvents, permitting cautious predictions. When applied to known effective concentrations of some solvents on human performance and subjective state, the comparative potency procedure suggests that ceiling and STEL values of some solvents may not reliably protect workers from acute nervous depression.

Abstract  Male Fischer or Porton-Wistar rats were exposed for 4 h to different atmospheric concentrations of CCl4 or were given increasing oral doses, of CCl4 in order to estimate isotoxic exposures or doses. Animals were killed 20 h after treatment, their serum glutamic-pyruvic transaminase activities were measured and their livers were processed for histological examination. It has been found that the equitoxic oral dose in Wistars is 1.5 times that in Fischer rats and more than 3 times after inhalation. Therefore, the conversion factors from inhalation exposure to oral dose were much higher for Fischer than for Porton-Wistar rats. After oral dosing, the extent of centrilobular damage in Fischer rats was approximately twice that in Porton-Wistar rats. After inhalation exposure, the extent of damage was the same in the two strains, but at least at the two lower exposure levels hydropic degeneration definitely contributed to the size of the damaged areas more in Porton-Wistar than in Fischer rats.

Abstract  Rats, guinea pigs, dogs, rabbits, and monkeys were exposed to trichloroethylene, carbon tetrachloride, 1,1,1-trichloroethane, dichlorodifluoromethane, and 1,1-dichloroethylene. Two types of inhalation experiments were conducted: continuous exposure for 90 days and 8-hour exposures, 5 days a week, for a total of thirty exposures. The parameters studied included mortality, visible signs of toxicity, and hematologic, biochemical, pathologic, and body weight changes. Throughout this entire study which encompassed 17 separate exposures over a period of nearly four years, no visible signs of toxicity were noted in any species exposed to these materials. Significant mortality was found in both the repeated (515 mg/m3) and continuous (61 mg/m3) exposures to carbon tetrachloride as well as in the continuous exposures to 1,1-dichloroethylene at 189, 101, and 61 mg/m3. Growth depression in varying degrees was found in all continuous exposures involving trichloroethylene, carbon tetrachloride, and 1,1-dichloroethylene and in the repeated exposures to carbon tetrachloride. No significant hematologic alterations were noted in any of the studies. No biochemical studies were done in the earlier years and hence no biochemical data were obtained from the animals exposed to trichloroethylene and dichlorodifluoromethane. Serum urea nitrogen levels were within control limits in all of the exposures to carbon tetrachloride, 1,1-dichloroethylene, and 1,1,1-trichloroethane in which determinations were made. Liver lipid contents in guinea pigs were found to be significantly elevated following repeated exposure to 515 mg/m3 of carbon tetrachloride. Significant elevations of serum glutamic-pyruvic transaminase and liver alkaline phosphatase activities were found in rats and guinea pigs following continuous exposure to 189 mg/m3 of 1,1-dichloroethylene. Histopathologic study revealed liver damage following continuous exposures to high levels of dichlorodifluoromethane (3997 mg/m3), and to lower levels of carbon tetrachloride (61 mg/m3), and 1,1-dichloroethylene (189 mg/m3). Similar liver damage was also found in the repeated exposures to the two latter materials at 515 mg/m3 and 395 mg/m3, respectively.

Abstract  There are many well documented similarities in the anatomy and physiology of mammalian species. There are also numerous examples in which the equilibrium distribution of foreign chemicals in the body appears to follow principles of thermodynamic partitioning with relatively minor interspecies variations to be expected. Information on metabolic pathways and their kinetic characteristics can be obtained from a variety of in vitro systems. It may be possible to use such information in pharmacokinetic models that incorporate existing knowledge and judgment to predict pharmacokinetics in intact animals including man.

Abstract  HEEP COPYRIGHT: BIOL ABS. Excessive leukemia mortality has appeared consistently in epidemiological studies of British and USA rubber industry workers. Attempts to identify causative factors have focused on exposure to benzene and other solvents. Interpretations of findings from these studies have often been influenced by expectations of a benzene/nonlymphocytic leukemia association, seen from previous work in other settings. However, data from the rubber industry studies have not been consistent with this expectation, as lymphocytic and nonlymphocytic leukemia have shown similar mortality excesses. Data from a small case-control study of lymphocytic leukemia are presented to illustrate an approach that considers multiple solvent exposures. The associations with lymphocytic leukemia risk observed for a number of solvents, most notably carbon tetrachloride and carbon disulfide, were stronger than those detected for benzene.

Abstract  The effect of acetone (67641) on trichloroethylene (79016) and carbon-tetrachloride (56235) hepatotoxicity was studied in rats. Male Sprague-Dawley-rats were administered 0, 0.25, 0.75, or 1.5 milliliters per kilogram (ml/kg) acetone orally. Eighteen hours later they were injected intraperitoneally with 0 or 0.25ml/kg trichloroethylene or 0.1 or 0.6ml/kg carbon-tetrachloride alone or in combination. The rats were killed 24 hours later, the livers were removed, and assayed for hepatotoxicity by determining plasma alanine-aminotransferase (ALT) activity, total bilirubin, and by histological examination. Acetone alone or combined with trichloroethylene had no effect on ALT activity or total bilirubin. ALT activity was higher in rats treated with trichloroethylene plus either dose of carbon-tetrachloride than with carbon-tetrachloride alone. Bilirubin concentration was increased only by trichloroethylene plus 0.6ml/kg carbon-tetrachloride. Acetone enhanced carbon-tetrachloride liver injury to a greater extent than trichloroethylene. Acetone markedly potentiated liver injury induced by trichloroethylene plus carbon-tetrachloride in a dose/dependent manner. Histological analyses showed no statistical differences in the percentages of normal, degenerated, or necrotic hepatocytes between carbon-tetrachloride or trichloroethylene treated rats and controls. Trichloroethylene plus carbon-tetrachloride significantly reduced the percentage of normal hepatocytes and increased the percentage of degenerated or necrotic hepatocytes. Acetone pretreated rats given the carbon-tetrachloride plus trichloroethylene mixtures showed a significant dose related decrease in the percentage of normal hepatocytes and a dose related increase in the percentage of necrotic hepatocytes. The authors conclude that trichloroethylene can potentiate carbon-tetrachloride induced liver injury. Acetone exerts a potentiating effect on the hepatotoxic response of the carbon-tetrachloride plus trichloroethylene mixtures.

Abstract  We review the experimental evidence for various shapes of dose-response relationships for carcinogens and summarize those experiments that give the most information on relatively low doses. A brief review of some models is given to illustrate the shapes of dose-response curve expected from them. Our major interest is in the use of dose-response relationships to estimate risks to humans at low doses, and so we pay special attention to experimentally observed and theoretically expected nonlinearities. There are few experimental examples of nonlinear dose-response relations in humans, but this may simply be due to the limitations in the data. The several examples in rodents, even though for high dose data, suggest that nonlinearity is common. In some cases such nonlinearities may be rationalized on the basis of the pharmacokinetics of the test compound or its metabolites.

Abstract  The present research was conducted to evaluate the effect of mitogen pre-exposure on CCl4-induced hepatotoxicity. Male Wistar rats were administered a single i.p. injection of CCl4 (0.3 ml kg-1 in corn oil) 48 h following either a single dose of lead nitrate (0.33 mg kg-1) or distilled water via i.v. injection. Hepatotoxicity, as measured by serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, was monitored 6, 24, 48, 72 and 120 h after CCl4 exposure. The lead nitrate-pretreated rats displayed markedly lower serum ALT and AST levels at 24, 48 and 72 h than rats pretreated with distilled water. However, treatment with the antimitotic agent colchicine did not alter the lead-induced protection. These findings suggest that the lead-induced protection is not associated with the major mitogenic response of lead, despite its strong temporal association. A critical review of the available toxicological data also argues against the lead protection being a function of its capacity to inhibit cytochrome P-450.

Abstract  Pesticides are associated with excess risk of multiple myeloma, albeit inconclusively. We included 678 men (30-94 years) from a well-characterized prospective cohort of restricted-use pesticide applicators to assess the risk of monoclonal gammopathy of undetermined significance (MGUS). Serum samples from all subjects were analyzed by electrophoresis performed on agarose gel; samples with a discrete or localized band were subjected to immunofixation. Age-adjusted prevalence estimates of MGUS were compared with MGUS prevalence in 9469 men from Minnesota. Associations between pesticide exposures and MGUS prevalence were assessed by logistic regression models adjusted for age and education level. Among study participants older than 50 years (n = 555), 38 were found to have MGUS, yielding a prevalence of 6.8% (95% CI, 5.0%-9.3%). Compared with men from Minnesota, the age-adjusted prevalence of MGUS was 1.9-fold (95% CI, 1.3- to 2.7-fold) higher among male pesticide applicators. Among applicators, a 5.6-fold (95% CI, 1.9- to 16.6-fold), 3.9-fold (95% CI, 1.5- to 10.0-fold), and 2.4-fold (95% CI, 1.1- to 5.3-fold) increased risk of MGUS prevalence was observed among users of the chlorinated insecticide dieldrin, the fumigant mixture carbon-tetrachloride/carbon disulfide, and the fungicide chlorothalonil, respectively. In summary, the prevalence of MGUS among pesticide applicators was twice that in a population-based sample of men from Minnesota, adding support to the hypothesis that specific pesticides are causatively linked to myelomagenesis.

Abstract  Well-defined nanoporous palladium (np-Pd) fabricated by a modified electrochemical dealloying procedure is demonstrated to be an excellent electrocatalyst material for reductive degradation of both carbon tetrachloride and chlorobenzene.

Abstract  Adsorption isotherms of chlorobenzene, chloroform and carbon tetrachloride vapors on undoped SiO(2), and metal-doped Ag/SiO(2), Cu/SiO(2) and Fe/SiO(2) substrates were measured in the temperature range of 398-593K. These substrates were prepared from a typical sol-gel technique in the presence of metal dopants that rendered an assortment of microporous-mesoporous solids. The relevant characteristic of these materials was the different porosities and micropore to mesopore volume ratios that were displayed; this was due to the effect that the cationic metal valence exerts on the size of the sol-gel globules that compose the porous solid. The texture of these SiO(2) materials was analyzed by X-ray diffraction (XRD), FTIR, and diverse adsorption methods. The pore-size distributions of the adsorbents confirmed the existence of mesopores and supermicropores, while ultramicropores were absent. The Freundlich adsorption model approximately fitted the chlorinated compounds adsorption data on the silica substrates by reason of a heterogeneous energy distribution of adsorption sites. The intensity of the interaction between these organic vapors and the surface of the SiO(2) samples was analyzed through evaluation of the isosteric heat of adsorption and standard adsorption energy; from these last results it was evident that the presence of metal species within the silica structure greatly affected the values of both the amounts adsorbed as well as of the isosteric heats of adsorption.

Abstract  Oxidative stress stimulates fibrogenesis, and selenium (Se) has antioxidant properties. This study determined whether Se supplementation affects CCl(4)-induced liver injury and fibrosis. Mice were administered CCl(4) over 4 weeks, while controls received olive oil. Se was provided as sodium selenite in the drinking water. Se increased liver Se-dependent glutathione peroxidase activity and decreased liver malondialdehyde after CCl(4). Se decreased liver inflammation but not necrosis caused by CCl(4). Se increased hepatocyte apoptosis after CCl(4) and the pro-apoptotic BAX and Bcl Xs/l proteins. Stellate cell apoptosis occurred only after CCl(4) in Se-supplemented mice. Se decreased stellate cell number and fibrosis after CCl(4). Liver matrix metalloproteinase-9 increased after CCl(4) with Se supplementation. In conclusion, Se supplementation decreased hepatic fibrosis after CCl(4) in the setting of decreased inflammation but increased apoptosis. The principal mechanisms for the decreased fibrosis are a lower number of collagen-producing stellate cells and increased collagen degradation.

Abstract  This position paper delineates the expert recommendations of the Regulatory Affairs Committee of the American Society for Veterinary Clinical Pathology for the use of preclinical, clinical pathology endpoints in assessment of the potential for drug-induced hepatic injury in animals and humans. Development of these guidelines has been based on current recommendations in the relevant preclinical and human clinical trial literature; they are intended to provide a method for consistent and rigorous interpretation of liver-specific data for the identification of hepatic injury in preclinical studies and potential liability for hepatic injury in human patients.