Effect of agents which modify reticuloendothelial system function on acute phalloidin-induced lethality and hepatotoxicity in mice.
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Animals↗
Biomedical subjects
E J Calabrese
Publications and source records attributed to E J Calabrese.
A review of the role of tissue repair as an adaptive strategy: why low doses are often non-toxic and why high doses can be fatal.
The role of tissue repair as an adaptive strategy by species is important to consider in both evolutionary and toxicological perspectives. This paper assesses the distinct and integrative roles of early phase regeneration (EPR) (i.e. arrested G2 hepatocytes chemically activated to proceed through mitosis) and secondary phase regeneration (SPR) (i.e. hepatocytes mobilized principally from G0/G1 to proceed through mitosis) in the repair of carbon tetrachloride (CCl4)-induced liver damage. The role of EPR as a triage system facilitating repair of minor toxic insults as well as providing an essential role in autoprotection as an initial step to augment and sustain SPR is proposed. The function of EPR is then compared with that of SPR in tissue recovery following more massive injury. The interrelationships of these two repair processes with EPR invoking and accelerated SPR following low-to-modest degrees of toxicant-induced hepatotoxicity as well as in auto- or hetero-protection supports the theory that the two responses are co-ordinated in time and functionality. The integration of these two repair processes as shown through experimental manipulation provides a new mechanistic framework to account for the previously reported profound (67-fold) potentiation of acute CCl4 hepatotoxicity by chlordecone (kepone) in adult male Sprague-Dawley rats as well as important interspecies variation in susceptibility to hepatotoxic agents in general and CCl4 in particular. On the basis of the distinct and integrative roles of EPR and SPR in liver responses to toxic injury, a generalized framework is presented that facilitates prediction of both toxic outcome, including shape of dose-response functions and interspecies variation to chemically induced liver damage.
Animals↗
Biological effects of low level exposures.
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Animals↗
Toxicological consequences of multiple chemical interactions: a primer.
The capacity to understand and successfully predict the toxicological consequences of multiple chemical interactions is a critical challenge facing the scientific community. This article is designed to provide a broad framework introducing the concept of interaction, use of consistent and meaningful terminology and a descriptive assessment of toxicological foundations within which chemical interactions may be evaluated. The article offers guidance on the need to place a high priority on assessing the mechanistic basis of 'superinteractions', that is, unique interactions far exceeding even those of a multiplicative nature. The final section of the article provides a detailed perspective on how the extensive and successful experience of the pharmaceutical industry in assessing and interpreting any interaction for patients can be useful to the issues and concerns of chemical interactions for the field of environmental toxicology and risk assessment.
Animals↗
A dog's tale: soil ingestion by a canine.
A single Irish Setter pet dog had its soil ingestion behavior quantitatively estimated on 3 consecutive days via a soil tracer-based mass-balance methodology. The results indicated a high agreement among the eight tracers (Al, Si, Ti, Y, Zr, La, Ce, and Nd) employed to estimate soil ingestion. The estimated daily soil ingestion rate ranged from approximately 10 to 20 g/day depending on the tracer. This represents a value far exceeding soil ingestion reported by an "average" child (ranging from 30 to 50 mg/day). The several hundred-fold higher soil ingestion rate in this dog compared to soil ingestion by an average child suggests the need to evaluate more fully soil and dust ingestion in domestic animals and wildlife especially with respect to potential exposure to contaminants in soil.
Animals↗
Susceptibility of mink to methemoglobin formation.
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Analysis of Variance↗
Daily estimates of soil ingestion in children.
Soil ingestion estimates play an important role in risk assessment of contaminated sites, and estimates of soil ingestion in children are of special interest. Current estimates of soil ingestion are trace-element specific and vary widely among elements. Although expressed as daily estimates, the actual estimates have been constructed by averaging soil ingestion over a study period of several days. The wide variability has resulted in uncertainty as to which method of estimation of soil ingestion is best. We developed a methodology for calculating a single estimate of soil ingestion for each subject for each day. Because the daily soil ingestion estimate represents the median estimate of eligible daily trace-element-specific soil ingestion estimates for each child, this median estimate is not trace-element specific. Summary estimates for individuals and weeks are calculated using these daily estimates. Using this methodology, the median daily soil ingestion estimate for 64 children participating in the 1989 Amherst soil ingestion study is 13 mg/day or less for 50% of the children and 138 mg/day or less for 95% of the children. Mean soil ingestion estimates (for up to an 8-day period) were 45 mg/day or less for 50% of the children, whereas 95% of the children reported a mean soil ingestion of 208 mg/day or less. Daily soil ingestion estimates were used subsequently to estimate the mean and variance in soil ingestion for each child and to extrapolate a soil ingestion distribution over a year, assuming that soil ingestion followed a log-normal distribution.
Child, Preschool↗
Resolving intertracer inconsistencies in soil ingestion estimation.
In this article we explore sources and magnitude of positive and negative error in soil ingestion estimates for children on a subject-week and trace element basis. Errors varied among trace elements. Yttrium and zirconium displayed predominantly negative error; titanium and vanadium usually displayed positive error. These factors lead to underestimation of soil ingestion estimates by yttrium and zirconium and a large overestimation by vanadium. The most reliable tracers for soil ingestion estimates were aluminum, silicon, and yttrium. However, the most reliable trace element for a specific subject-day (or week) would be the element with the least error during that time period. The present analysis replaces our previous recommendations that zirconium and titanium are the most reliable trace elements in estimating soil ingestion by children. This report identifies limitations in applying the biostatistical model based on data for adults to data for children. The adult-based model used data less susceptible to negative bias and more susceptible to source error (positive bias) for titanium and vanadium than the data for children. These factors contributed significantly to inconsistencies in model predictions of soil ingestion rates for children. Correction for error at the subject-day level provides a foundation for generation of subject-specific daily soil ingestion distributions and for linking behavior to soil ingestion.
Adult↗
Tissue repair: a critical determinant in CCl4 hepatotoxicity.
A single antimitotic dose of colchicine administered 24 hr after a single ip dose of CCl4 profoundly enhanced lethality in the adult Sprague-Dawley male rat from < 10% to over > or = 70% within the next 24 hr. These findings suggest that disruption of normal hepatic cellular repair processes is a critical factor affecting the outcome of CCl4 intoxication.
Animals↗
Gap junction-mediated intercellular communication in primary cultures of rainbow trout hepatocytes.
Gap junction-mediated intercellular communication was evaluated in primary cultures of rainbow trout hepatocytes by measurement of dye coupling. Donor hepatocytes were microinjected with fluorescent Lucifer yellow CH dye and visualization of dye spread (dye coupling) to adjacent hepatocytes was recorded. A maximum level was reached between 8 and 12 hr which was maintained up to 24 hr. Dye coupling then decreased over the next 48 hr. Cell viability was monitored by the percentage of total LDH released and trypan blue exclusion at each time point. The effect of 12-O-tetradecanoylphorbol-13-acetate (TPA), a known inhibitor of rodent hepatic intercellular communication, on gap junction-mediated intercellular communication was evaluated in 24-hr cultures. A dose-response inhibition was demonstrated with maximum inhibition observed at 3 hr of exposure.
Animals↗
Improved method for selection of the NOAEL.
The paper proposes that the NOAEL be defined as the highest dosage tested that is statistically significantly different from the control group while also being statistically significantly different from the LOAEL. This new definition requires that the NOAEL be defined from two points of reference rather than the current approach (i.e., single point of reference) in which the NOAEL represents only the highest dosage not statistically significantly different from the control group. This proposal is necessary in order to differentiate NOAELs which are statistically distinguishable from the LOAEL. Under the new regime only those satisfying both criteria would be designated a true NOAEL while those satisfying only one criteria (i.e., not statistically significant different from the control group) would be designated a "quasi" NOAEL and handled differently (i.e., via an uncertainty factor) for risk assessment purposes.
Dose-Response Relationship, Drug↗
Evaluation of a rodent peroxisome proliferator in two species of freshwater fish: rainbow trout (Onchorynchus mykiss) and Japanese medaka (Oryzias latipes)
Rainbow trout (Onchorynchus mykiss) and Japanese medaka (Oryzias latipes) were exposed to the hypolipidemic drug gemfibrozil, a known rodent peroxisome proliferator. Trout were injected (i.p.) daily for 2 weeks at doses of 0, 46, 87, or 152 mg/kg/day. Medaka were exposed to the nominal concentrations of 0, 1.25, 2.5, or 5 ppm in water for 2 weeks in a static-renewal system. Peroxisome proliferation was assessed by measuring fatty acyl-CoA oxidase (FAO) activity, peroxisomal bifunctional enzyme (PBE) quantity, and changes in liver-to-body weight ratios (LWR). Results indicate that a mild peroxisome proliferative response was observed in rainbow trout (significant increases in FAO activity at all dose levels and in LWR at the highest dose level). Medaka demonstrated a significant increase in PBE at the highest dose level, while nonsignificant increases in FAO activity were observed at the mid- and high-dose levels.
Animals↗
Selective inhibition of gastrointestinal beta-glucuronidase by poly(vinylbenzyl D-glucaro(1,4)lactonate). Part 2. Poly(vinylbenzyl D-glucaro(1,4) lactonate) in vitro inhibition studies.
In vitro inhibition studies with beta-glucuronidase from purified E. coli and mouse intestinal contents indicated that the polymer, poly(vinylbenzyl D-glucaro(1,4)lactonate, is an effective beta-glucuronidase inhibitor. Purified E. coli beta-glucuronidase was inhibited by 99.6% with 177 mM D-glucaro(1,4)lactone using the polymer-inhibitor. Similarly, 95% inhibition of beta-glucuronidase activity of mouse intestinal contents was obtained with 177 mM and 50% inhibition was obtained with 31.5 mM D-glucaro(1,4)lactone based on the modified polymer. The structural requirements of an effective beta-glucuronidase inhibitor based on the structure of the polymer-inhibitor are also discussed.
Animals↗
A toxicological basis to derive a generic interspecies uncertainty factor.
A new method is proposed to derive the size of the interspecies uncertainty factor (UF) that is toxicologically and statistically based. The method involves quantifying interspecies variation in susceptibility to numerous toxic substances via the use of binary interspecies comparisons that are converted to a 95% UF. This interspecies UF represents an estimate of the upper 95% of the population of 95% prediction intervals (PI) for binary interspecies comparisons within four categories of phylogenetic relatedness (species within genus, genera within family, families within order, orders within class). The 95% interspecies UFs range from a low of 10 for species within genus up to 65 for orders within class. Most mammalian toxicology studies involving mice, rats, cats, dogs, gerbils, and rabbits are orders-within-class categories for human risk assessment and would be provided a 65-fold UF. Larger or smaller interspecies UF values could be selected on the level of protection desired.
Animals↗
Ornithine decarboxylase (ODC) activity in the liver of individual medaka (Oryzias latipes) of both sexes.
Ornithine decarboxylase (ODC) activity has been determined in the liver of individual medaka (N = 48). The results indicate a mean ODC activity of 1.69 +/- 1.77 nmol 14CO2/hr/mg protein. The fish displayed a large interindividual variation of normal ODC activity with a range of 140fold. However, no sex differences were observed. The findings also indicate that the mean ODC activity in this fish model is approximately 100fold greater than observations in the published literature as well as in our laboratory for commonly employed rodent models.
Animals↗
The effect of peroxisome proliferators on S-phase synthesis in primary cultures of fish hepatocytes.
The ability of seven structurally diverse peroxisome proliferators to induce S-phase synthesis was studied in primary cultures of rainbow trout and medaka hepatocytes. Cells were maintained in serum-free conditions designed to facilitate attachment, viability, and function. Lead nitrate, a well-known and potent rodent liver mitogen, was used in vitro in trout and medaka and in vivo in trout to evaluate the capacity of the species and our system to respond to mitogenic stimuli. S-phase synthesis induced by peroxosome proliferators did not result in any statistically significant increase over control cultures. These in vitro results are supported by in vivo data previously obtained and the present work with lead nitrate.
Animals↗
Effect of hypolipidemic drugs gemfibrozil, ciprofibrate, and clofibric acid on peroxisomal beta-oxidation in primary cultures of rainbow trout hepatocytes.
Primary cultures of hepatocytes were established from sexually mature male rainbow trout (Oncorhyncus mykiss) and treated with the hypolipidemic drugs gemfibrozil (0.25-1.25 mM), clofibric acid (2.25-3.00 mM), or ciprofibrate (0.25-1.00 mM). Significant dose-related increases in peroxisomal fatty acyl-CoA oxidase (FACO) were seen after exposure for 48 hr to clofibric acid (P < 0.01) and ciprofibrate (P < 0.05) but not gemfibrozil (P = 0.08). Strong correlation was obtained between increased acyl-CoA oxidase activity and the relative amount of peroxisomal bifunctional enzyme (PBE), further supporting evidence of a proliferative effect. These preliminary studies demonstrate that peroxisomal beta-oxidation can be induced in vitro in a primary rainbow trout hepatocyte system.
3-Hydroxyacyl CoA Dehydrogenases↗
Comparative response of rainbow trout and rat to the liver mitogen, lead.
Lead nitrate and acetate are potent liver mitogens in the Wistar rat. Prior exposure to these agents has been found to alter their susceptibility to hepatotoxins. The present study assessed the capacity of both lead compounds to cause mitogenicity in the liver of adult male and female rainbow trout. Groups treated with a single intravenous or intraperitoneal injection of lead nitrate or lead acetate exhibited no statistically significant (P < 0.05) alterations in liver/body weight ratio nor hepatic DNA content. Results provide evidence of significant interspecies variation in the mitogenic response of rainbow trout and Wistar rats to the mitogenic potential of lead in the liver.
Animals↗