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Biomedical subjects

C C Travis

Publications and source records attributed to C C Travis.

At least 19 recordsLinked to original sources
PubMed1992

Co-exposure to gasoline vapor decreases benzene metabolism in Fischer-344 rats.

The metabolic interactions of benzene and gasoline vapor were investigated in male Fischer-344 rats. A closed chamber gas-uptake exposure system was used to obtain inhalation uptake curves for benzene alone and benzene in the presence of gasoline vapor. Exposure to benzene as a component of gasoline vapor resulted in a decrease of benzene metabolism. A physiologically based pharmacokinetic model of benzene metabolism was used to quantitatively determine the extent of the inhibitory effect of gasoline vapor on benzene metabolism. This observed inhibitory effect cannot be accounted for by the presence of toluene in gasoline vapor.

Animals↗
PubMed1992

Promotion as a factor in carcinogenesis.

Promotion is any factor which results in the increased cellular replication of initiated or transformed cells. We argue that cytotoxicity is not a necessary component of promotion and that, therefore, the existence of a threshold for promotion is unlikely.

Animals↗
PubMed1991

Diethylnitrosamine-induced hepatocarcinogenesis in rats: a theoretical study.

Multiple data sets on hepatocarcinogenesis in rats resulting from pulse (single) or continuous exposure to diethylnitrosamine (DEN) are analyzed within the framework of a two-mutation carcinogenesis model in order to identify the underlying biological processes that control the pharmacodynamics of DEN-induced liver cancer. Our findings indicate: (1) Predictions of the two-mutation oncogenic model are consistent with empirical data on DEN-induced hepatocarcinogenesis. (2) The probability of the first genetic alteration (initiation) is linearly dependent on applied dose and decays exponentially following a pulse (single) dose or cessation of exposure. (3) The probability of initiation is proportional to the number of O4-ethyldeoxythymidine DNA adducts resulting from DEN exposure, indicating that these adducts are the likely promutagenic lesions in DEN-induced hepatocarcinogenesis. (4) The mitotic rates of initiated and transformed cells are nonlinear with dose. (5) The average growth rate of initiated hepatocytes as a function of DEN dose is related to Druckery's slope. (6) The probability of the second genetic event (transformation) is independent of applied dose, suggesting that it is the result of a spontaneous genetic alteration.

Animals↗
PubMed1991

Human exposure to dioxin.

Because 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent chemical carcinogen evaluated by the U.S. Environmental Protection Agency (EPA), many people fear that exposure to even small amounts of TCDD could lead to serious health effects. Ambient measurements confirm that environmental TCDD contamination is widespread. The public is concerned about TCDD exposure from such diverse sources as municipal solid waste incinerators, pulp and paper mills, and contaminated fish and soil. This paper evaluates several critical issues including: (i) the extent of background contamination; (ii) accumulation in the food chain and the potential for human exposure from ingesting contaminated food items; (iii) the magnitude of TCDD emissions into the U.S. environment, and the relative contribution of various known TCDD sources to the total TCDD load; and (iv) setting environmental standards for TCDD.

Animals↗
PubMed1991

Druckery slope controlled by mitotic rate of enzymatically-altered foci.

Data on hepatocellular foci and tumors for four hepatocarcinogens are analyzed within the framework of a two-mutation model of oncogenesis to determine the biological factor(s) that control the values of N in Druckery's formula DTN = K, where T is the time to 50% tumor incidence at a daily dose D. The two-mutation oncogenic model was found to adequately reproduce the empirical data for all four hepatocarcinogens. The controlling factor of the Druckery slope N was found to be the mitotic rate (MRI) of hepatocellular foci, where MRI = CD1/N, C is a chemical-dependent constant, D is dose, and N is the Druckery slope.

Animals↗
PubMed1991

Sensitivity analysis for physiologically based pharmacokinetic models.

The present study evaluates the sensitivity of pharmacokinetic model output to variability in the biochemical and metabolic input parameters. Pharmacokinetic models of three chemicals are chosen for analysis: styrene, methylchloroform, and methylene chloride. Results show that model sensitivities are time-, dose-, and species-dependent and that the most sensitive parameters are the maximum Michaelis-Menten metabolism rate Vmax and the blood/air and fat/air partition coefficients. For humans, the muscle/air partition coefficient is also important. Model output is insensitive to the Michaelis-Menten parameter Km (except for low doses) and to other tissue/air partition coefficients.

Administration, Inhalation↗
PubMed1991

Quantitative correlation of carcinogenic potency with four different classes of short-term test data.

The search for a short-term mutagenicity test to identify potential carcinogens has yielded over 100 assay systems, including the Ames test. This paper continues the investigation of Travis et al. into the prediction of carcinogenic potency of known mouse carcinogens using different classes of short-term toxicologic data. We used four classes of short-term test data (mutation, toxicity, reproduction and tumorigenicity) from the Registry of Toxic Effects of Chemical Substances (RTECS) database. We conclude that mutation data alone are poor predictors of carcinogenic potency, accounting for only 21% of the observed variability in experimentally-determined mouse TD50 values. We further conclude that batteries of toxicologic data containing varying types of short-term data are excellent predictors of the carcinogenic potency of known mouse carcinogens: four types of short-term data account for 82% of the observed variability in experimentally-obtained mouse TD50 values. By using all available toxicological data, we obtained a strong correlation between toxicologic assay results and carcinogenic potency of known mouse carcinogens.

Animals↗
PubMed1991

Benzo-a-pyrene: environmental partitioning and human exposure.

A multimedia transport model was used to evaluate the environmental partitioning of benzo-a-pyrene (BaP). Measured and predicted environmental concentrations were used to estimate the accumulation of BaP in the food chain and the subsequent extent of human exposure from inhalation and ingestion. Results show that BaP partitions mainly into soil (82%) and sediment (17%) and that the food chain is the dominant pathway of human exposure, accounting for about 97% of the total daily intake of BaP. Inhalation and consumption of contaminated water are only minor pathways of human exposure. The long-term average daily intake of BaP by the general population of the U.S. is estimated to be 2.2 micrograms (micrograms) per day. Cigarette smoking and indoor activities do not substantially increase human exposure to BaP relative to exposures to background levels of BaP present in the environment. Since the increased lifetime risk associated with human exposure to background levels of BaP is 3.5 x 10(-4), we conclude that ingestion of food items contaminated with BaP may pose a serious health threat to the U.S. population.

Animals↗
PubMed1991

Interspecies scaling of anesthetic potency.

Anesthetic potency data for 11 volatile anesthetics were correlated against body weight in multiple mammalian species, including man. The results indicate that the alveolar concentration necessary to produce anesthesia is approximately constant across species. Because alveolar ventilation rates scale with the 0.75 power of body weight, this implies that administered dose measured in mg/kg0.75/day produces the same anesthetic effect in all species. This analysis provides further support for the use of a mg/kg0.75/day interspecies scaling metric for acute toxic effects.

Anesthetics↗
PubMed1991

Interspecies extrapolation in risk analysis.

This report provides an overview of one of the fundamental problems in cancer risk assessment: extrapolation of observed experimental results between animal species and man. Lacking detailed information on interspecific differences, researchers assume that experimental results can be extrapolated between species using the first power of body weight or using surface area scaling (body weight to 2/3 power). Neither of these extrapolation procedures will be exactly correct for all compounds. However, in the absence of species-specific data, body weight or surface area extrapolations are used with the explicit knowledge that they are only approximately correct. We recommend that when a scaling metric for a specific compound is known, the scaling metric should be used in a risk assessment. When there is no prior knowledge of a chemical's pharmacokinetics or mechanism of action (the usual case in risk assessment), we recommend that the 3/4 power of body weight be used as the most appropriate interspecies scaling metric. The methods and properties used in interspecies extrapolation include allometric scaling, scaling physiological parameters (organ volumes, volume rates, partition coefficients, and biological half-life), physiological time, and physiologically-based pharmacokinetics. The extrapolation of these physiological, biochemical, and metabolic parameters across species controls interspecific extrapolation of pharmacokinetics. We analyzed clearance and half-life data for several compounds in multiple species and determined that the 3/4 power scaling law provides a more accurate estimate of a compound's true scaling metric than does the surface area scaling metric or the first power of body weight scaling metric.

Animals↗
PubMed1990

Pharmacokinetics of benzene.

A physiologically based pharmacokinetic model was developed and used to describe the pharmacokinetics of benzene in three species: mice, rats, and humans. For each species, the body was divided into five anatomical compartments, consisting of liver, fat, bone marrow, and muscle, and organs such as brain, heart, kidney, and viscera, connected by the arterial and venous blood flow pathways. Metabolism of benzene followed Michaelis-Menten (nonlinear) kinetics in all species and occurred primarily in the liver compartment and, to a lesser extent, in the bone marrow. Comparison of model results with empirical data on inhalation, gavage, and intraperitoneal and subcutaneous injection in mice, rats, and humans, demonstrates the utility of a physiological pharmacokinetic model in describing the pharmacokinetics of benzene in three species across multiple routes of exposure.

Animals↗
PubMed1990

Interspecies extrapolation of pharmacokinetics.

The purpose of this paper is to use physiologically based pharmacokinetic models to demonstrate that if toxic response is a function of the time profile in physiological time of the concentration of the toxic moiety in the target tissue, then the appropriate interspecies scaling law for toxic compounds which are metabolically deactivated is mg kg-1 per unit of physiological time (mg kg-1 pt-1). At low dose rates this metric is approximately equivalent to mg kg-0.75 day-1. For reactive metabolites which are spontaneously deactivated, an approximate interspecies scaling law is mg kg-1 day-1.

Animals↗
PubMed1990

Small-scale field test of the genetically engineered lacZY marker.

Commercial genetic engineering is advancing into areas that require the small-scale introduction of genetically engineered microorganisms (GEMs) to better quantify variables that affect microorganism distribution and survival and to document potential long-term consequences. A recombinant DNA marker system, the lacZY marker, developed by the Monsanto Agricultural Co., enables the distribution and fate of marked fluorescent pseudomonad organisms to be monitored under actual field conditions. Critical evaluation of GEMs under field conditions is imperative if plant-beneficial effects are to be correlated with organism release. This paper evaluates the effectiveness of this marker system and its ability to facilitate the assessment of risks associated with deliberate environmental introductions of genetically engineered microorganisms. Results of prerelease contained growth chamber and field experiments demonstrated that: (1) the scientific risk assessment methodology adopted by Monsanto and approved by the U.S. Environmental Protection Agency was appropriate and comprehensive; (2) the deliberate introduction of a GEM did not pose unacceptable or unforeseen risks to human health or the environment; (3) the lacZY marker is an effective environmental tracking tool; and (4) regulatory oversight should reflect the expected risk and not be excessively burdensome for all GEMs.

DNA, Recombinant↗
PubMed1990

In vivo metabolic interactions of benzene and toluene.

The metabolic interactions of benzene and toluene co-exposure were investigated in male Fischer rats. A closed recirculated exposure system was used to obtain inhalation uptake curves for individual chemicals as well as for a mixture of the two compounds. Pharmacokinetic parameters for benzene and toluene individually were determined in previous experimental studies. These values were incorporated into a physiologically based pharmacokinetic model which simulated the inhalation uptake process for both chemicals simultaneously. An optimal fit to the uptake curves for simultaneous exposure was obtained by adjusting the metabolic interaction terms for each chemical. Mutual suppression of metabolism was apparent. Toluene more effectively inhibited benzene metabolism than the reverse. This simulation approach for analyzing gas uptake data provided a method to determine the metabolic interactions occurring upon inhalation exposure to two different chemicals. Such analyses will prove useful in improving predictive toxicokinetic models.

Animals↗