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Biomedical subjects

A M Schumann

Publications and source records attributed to A M Schumann.

15 recordsLinked to original sources
PubMed1996

In vivo and in vitro studies of perchloroethylene metabolism for physiologically based pharmacokinetic modeling in rats, mice, and humans.

In vivo experiments in rats and mice and in vitro experiments in rats, mice, and humans have been used to develop and validate a "2nd generation" physiologically based pharmacokinetic (PBPK) model for perchloroethylene (PERC). The refined PBPK model should be useful in the preparation of carcinogenic risk assessment based on amounts of PERC metabolites formed in the livers of rodents and humans according to procedures developed by EPA. A sensitivity analysis of the PBPK model revealed that the most significant uncertainties in this process (other than the choice of the appropriate dose/response model based on mechanism of action of PERC) were in the techniques used to estimate rates of PERC metabolism in humans. In vitro studies with human tissues reported help define what some have called the range of "equally reasonable alternatives" for estimating human risk.

Administration, Inhalation↗
PubMed1990

Mutational analysis of the H-ras oncogene in spontaneous C57BL/6 x C3H/He mouse liver tumors and tumors induced with genotoxic and nongenotoxic hepatocarcinogens.

The frequency and mutational profile of H-ras gene activation were determined in spontaneous liver tumors of male C57BL/6 x C3H/He mice and in tumors induced with the genotoxic hepatocarcinogen benzidine.2 HCl or the nongenotoxic hepatocarcinogens phenobarbital, chloroform, and ciprofibrate. DNA sequence analysis of the H-ras gene from representative tumors revealed that 32 of 50 (64%) spontaneous tumors and 13 of 22 (59%) benzidine.2 HCl-induced tumors contained a point mutation in codon 61. Tumors induced with the nongenotoxic agents had a much lower frequency of codon 61 mutations, i.e., phenobarbital, 1 of 15 (7%); chloroform, 5 of 24 (21%), and ciprofibrate, 8 of 39 (21%). No mutations were observed at codons 12, 13, and 117 in tumors from any of the groups. Only three base pair substitutions within codon 61 were found. The one most frequently detected in all of the groups was a C.G to A.T transversion at the first nucleotide position, occurring at a 59%, 85%, 100%, 80%, and 88% frequency in the spontaneous tumors and in the tumors induced with benzidine 2.Hcl, phenobarbital, chloroform, and ciprofibrate, respectively. In these same groups an A.T to G.C transition or an A.T to T.A transversion at the second nucleotide position occurred at a frequency of 34%, 8%, 0%, 0%, and 12%, and 6%, 8%, 0%, 20%, and 0%, respectively. The number of tumors carrying an activated H-ras gene in the nongenotoxic treatment groups is within the range that would be expected if those animals had not received any treatment. This indicates that the activation of the H-ras gene in those tumors is probably the result of a spontaneous event. The data suggest that these toxicologically and pharmacologically diverse nongenotoxic hepatocarcinogens increase the frequency of liver tumors but do not induce mutations in the H-ras gene. Instead these agents appear to interact with a population of cells that do not contain an activated H-ras gene. This suggests that the mechanisms of tumor development by these nongenotoxic carcinogens differ at least partially from the mechanisms responsible for the development of spontaneous tumors or those induced by a typical genotoxic agent.

Animals↗
PubMed1989

Metabolism and disposition of ethylene carbonate in male Fischer 344 rats.

Ethylene carbonate (EC) has a toxicity profile which resembles that of ethylene glycol (EG). To determine whether the toxicity of EC could be explained on the basis of its metabolism to EG, male Fischer 344 rats were given 200 mg/kg of uniformly labeled [14C]EC in water by gavage and the disposition of the radiolabel was then followed for 72 hr. EC was rapidly metabolized, with approximately 57 and 27% of the administered dose eliminated in the expired air as 14CO2 and in the urine, respectively; the remainder was found in the carcass. Separation of the urinary metabolites using liquid chromatography revealed a single radioactive peak. This metabolite was unequivocally identified as ethylene glycol via gas chromatography-mass spectrometry with the aid of 13C enrichment of the EC dose. Measurement of whole blood levels of EC and EG in rats given 200 mg/kg of EC by gavage revealed blood levels of EG approximately 100-fold higher than the levels of EC in these same animals, with a half-life of EG in blood of 2 hr, indicating rapid conversion of EC to EG. In a separate group of animals administered an equimolar dose of [14C]EG (141 mg/kg), approximately 37% of the dose was expired as 14CO2 and 42% was excreted in the urine as parent compound. When expressed on the basis of the ethanediol moiety, the disposition of EC was identical to that of EG. In view of the rapid and extensive biotransformation of EC to EG and the similarity of the existing (though limited) toxicity data base of EC compared to EG, utilization of the extensive EG systemic toxicity data base for assessing the safety of EC appears justified.

Administration, Oral↗
PubMed1988

Physiologically based pharmacokinetic modeling with methylchloroform: implications for interspecies, high dose/low dose, and dose route extrapolations.

A unified physiologically based pharmacokinetic (PB-PK) model was developed and used to describe the disposition of methylchloroform (1,1,1-trichloroethane, MC) in three different species (rats, mice, and humans) after four different routes of exposure (inhalation, intravenous injection, bolus gavage, and drinking water administration). Metabolism of MC followed Michaelis-Menten kinetics in each species. Vmax's were calculated from the allometric equation: Vmax = 0.419 BW0.7, and Km appeared to be identical in each species (5.75 mg equivalents/liter). Once the PB-PK model had been developed for young adult animals (1-3 months of age), it was used to study the disposition of MC in older rats and mice (approximately 18.5 months of age). Most of the changes in the pharmacokinetic behavior of MC in older rats could be simulated by increasing the size of the fat compartment in the PB-PK model from 7 to 18% of body weight. However, the pharmacokinetic behavior in older mice was more complex; increasing the size of the fat compartment in this species from 4 to 18% only accounted for part of the observed differences between old and young animals. An appropriate dose surrogate (average area under the liver concentration/time curve) was selected and the PB-PK model was used to make quantitative comparisons between "internal doses" of MC in long term animal studies and "internal doses" associated with human exposures to MC. Values of the dose surrogate in humans consuming 2 liters/day of water with typical levels of MC contamination (1-10 ppb) were four to six orders of magnitude lower than the dose surrogates in the rodent studies at levels of MC exposure which failed to produce adverse effects on the liver (875-1500 ppm, 6 hr/day, 5 days/week).

Animals↗
PubMed1988

Toxicokinetics in the evaluation of toxicity data.

Toxicokinetics provides a powerful tool, which is not used sufficiently in the conduct and interpretation of animal toxicity studies. In selecting doses for toxicity studies toxicokinetic data can be used effectively. The tools of toxicokinetics are limited only by the toxicologists' understanding of basic biologic mechanisms. More knowledge on mechanisms of action implicates the possibility of more detailed toxicokinetic models. Physiologically based pharmacokinetic models are valuable in the interpretation of animal toxicity studies. They provide a physiological basis for extrapolating between species and routes of administration, and the future use of these models in setting acceptable levels of exposure for non-cancer toxicity in humans deserves serious consideration.

Animals↗
PubMed1987

Activation of a cellular proto-oncogene in spontaneous liver tumor tissue of the B6C3F1 mouse.

The controversy surrounding the interpretation of observed increases in the high spontaneous liver tumor incidence of the B6C3F1 mouse after administration of certain chemical agents necessitates a mechanistic understanding into the nature of tumor development in this particular strain of mouse. Recently, cancer genes (oncogenes) have been detected in the DNA from a variety of human tumors and tumor cell lines. These genes have been implicated to play a role in the transformation of normal cells into cancerous ones. To investigate the role that cellular oncogenes might play in the development of spontaneous liver tumors in the B6C3F1 mouse, DNA was isolated from spontaneously occurring liver tumors and transfected into NIH 3T3 fibroblasts. DNA from this tumor tissue was capable of transforming NIH 3T3 cells from 82% of the animals examined strongly suggesting the presence of an active cellular oncogene. In contrast, DNA isolated from surrounding non-tumorous liver tissue and liver tissue from non-tumor bearing mice did not cause any transformation in the NIH 3T3 assay. These data demonstrate that the active cellular oncogene is not present in the hepatic tissue via a germ-line transmission but is activated only in those cells of the tumor tissue. Experiments using Southern blot hybridization analysis have identified this active cellular oncogene to be a member of the ras oncogene family. Identification of this cellular oncogene will now allow the evaluation of factors which might modify its expression. These future studies will lead to an increased understanding of potential mechanisms by which hepatic tumors are enhanced and should provide more informed estimates of risk for man based on bioassay data generated in this strain of mouse.

Animals↗
PubMed1987

Research strategy in industrial toxicology.

While much of industrial toxicology is observational in character, pursuit of specific research is needed to facilitate the overall evaluation of potential toxicity for man. Two such areas are the application of physiologic pharmacokinetic models to inter-species extrapolation of toxic effects and an understanding of the role of cellular oncogenes in the process of spontaneous tumor formation in animals. A physiologic pharmacokinetic model was developed for methylene chloride (MeCl2) which describes the fate of MeCl2 and its metabolic products in numerous species including the mouse, rat, hamster and man. This model has been used to predict specific tissue concentrations of critical metabolic reaction products in target tissues between animals and man. If it is assumed that toxicity is related to target tissue concentrations such methodology provides a means of relating interspecies toxicity to absorbed dose. This methodology precludes the necessity of using arbitrary factors in relating animal toxicity data to man. A particular controversial issue in animal toxicology is the significance of the enhancement of animal tumors in tissues which already have a high spontaneous incidence. Without a better understanding of the basic process of spontaneous tumor formation it remains difficult to interpret results from chemical treatment. In particular spontaneous liver tumors in the B6C3F1 mouse have been shown to contain an activated cellular oncogene identified as H-RAS. The activated cellular oncogene is present in tumor tissue only and not in surrounding normal liver tissue. Of particular significance is the high frequency of activation in these mouse liver tumors (82%) compared to a 10-20% incidence of oncogenes present in a variety of human tumors. This suggests the ultra sensitivity of this mouse strain to liver tumor induction. Additional studies in progress are designed to determine whether genotoxic and nongenotoxic hepatocarcinogens show differences in oncogene activation.

Animals↗
PubMed1980

Non-linear pharmacokinetic parameters need to be considered in high dose/low dose extrapolation.

It is impossible to prove that any chemical, natural or man-made, cannot cause cancer in man. However, it is possible to estimate the relative degrees of risk associated with various agents. The precision of these estimations increases as experimental procedures elucidate the basic type of mechanism associated with carcinogenesis, the role of absorption, metabolism and distribution, and excretion in increasing or decreasing activity, and the dose dependency of metabolic pathways. We must constantly strive to make the most accurate risk estimations possible so that the complex issues of risk/benefit may be properly considered.

Alkylation↗