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C J Portier

Publications and source records attributed to C J Portier.

At least 19 recordsLinked to original sources
PubMed1995

Carcinoma formation in NMRI mouse skin painting studies is a process suggesting greater than two stages.

The two-stage model of carcinogenesis, which incorporates clonal growth of intermediate cells, has gained increasing attention in recent years. It was formulated to match tumor incidence data and expanded to encompass observations made in initiation-promotion carcinogenicity experiments. Mouse skin experiments are perceived as supporting this model, with papillomas representing the intermediate cells and carcinomas representing the malignant cells. In this manuscript, the two-stage model is applied to data concerning papilloma and carcinoma formation from an initiation-promotion NMRI mouse skin painting experiment which included stop-promotion. It is shown that the model is not compatible with these data if all papillomas are considered premalignant lesions. The model was modified to allow for a heterogeneous population of papillomas. In this case, unless one assumes that premalignant and terminally benign papillomas are morphologically different in the sense that both types of papillomas at detection limit contain distinct numbers of actively dividing initiated cells, the model predicts larger numbers of papillomas at the end of the experiment than were actually observed. The best explanation is that the model is not in accordance with these data and that the data indicate the need for stages between initiated and malignant cells.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Quantitative analysis of multiple phenotype enzyme-altered foci in rat hepatocarcinogenesis experiments: the multipath/multistage model.

The promotional effect of phenobarbital and 1-hydroxymethyl-pyren on enzyme altered lesions in the rat liver were quantified within the framework of two separate multipath/multistage models. The experiment analyzed followed an initiation-promotion protocol in which female Wistar rats were initiated with a single dose of diethylnitrosamine at 0.15 mumol/g body wt followed by a 3 week treatment-free period. A promotor, 1-hydroxymethyl-pyren or phenobarbital was then administered continuously in the diet for 120 days. All animals were sacrificed 3 weeks after treatment and their livers were examined for enzyme histological changes. Focal lesions were classified into three phenotype categories: adenosine triphosphatase altered (ATPase), sulfotransferase altered (ST) and jointly altered lesions (ATPase and ST). Quantitative methods were used to analyze the data, which consisted of the number and sizes of these enzyme-altered lesions. Both multipath/multistage models fitted to the data clearly demonstrate that phenobarbital promotion produced more observable and larger foci than promotion via 1-hydroxymethyl-pyren and that the growth kinetics of the jointly altered lesions were elevated relative to the lesions expressing a single marker. It was not possible with these data to determine if there was a predominant sequence in the formation of jointly altered lesions.

Adenosine Triphosphatases↗
PubMed1994

A stem cell model for carcinogenesis.

A modification to the well-known two-stage model of carcinogenesis with clonal expansion is proposed. A true stem cell is applied to the production of intermediate cells by incorporating a birth-death process with a reflecting barrier into the model. The distribution of the number of detectable intermediate cell clones is derived, and systems of differential equations are formulated for the cumulative distribution function for the appearance of malignant tumors. The model is applied to data on papilloma formation in a mouse skin painting experiment. Tests for the importance of intermediate cells in tumor incidence can be derived.

Animals↗
PubMed1994

The importance of biological realism in dioxin risk assessment models.

Mechanistic mathematical models of hepatocarcinogenesis in the female rat were constructed to investigate possible relationships among the Ah, estrogen, and EGF receptors in TCDD hepatocarcinogenicity. Each model generates dose-response curves for the expression of biomarker liver proteins CYP1A1, CYP1A2, and residual plasma membrane EGF receptor consequent to exposure to TCDD. The shapes of the response curves were strongly dependent on the assumed mechanisms of constitutive expression of these proteins. Assuming a constant level of the hepatic Ah receptor, a sigmoidal dose-response of hepatic CYP1A1 to total liver TCDD was computed. However, inclusion of induction of the Ah receptor by TCDD in a physiologically realistic dosimetric model produced a linear low-dose response of CYP1A1. This behavior was computed to arise from the net effect of sublinear response of CYP1A1 mRNA to the concentration of the Ah-TCDD complex and supralinear response of the protein concentration to the mRNA level, illustrating the importance of biological realism in dose-response modeling. The dosimetric model also computed effects of TCDD on the hepatic estradiol concentration and consequent effects on the binding capacity of the EGF receptor and suggests plausible mechanisms for tumor promotion by TCDD. Setting circulating estradiol levels in the model to values typical of the male rat indicated possible sources of the differences in the responses of the EGF receptor and in development of tumors in the two sexes.

Animals↗
PubMed1994

Multistage models of carcinogenesis: an approximation for the size and number distribution of late-stage clones.

Multistage models have become the basic paradigm for modeling carcinogenesis. One model, the two-stage model of carcinogenesis, is now routinely used in the analysis of cancer risks from exposure to environmental chemicals. In its most general form, this model has two states, an initiated state and a neoplastic state, which allow for growth of cells via a simple linear birth-death process. In all analyses done with this model, researchers have assumed that tumor incidence is equivalent to the formation of a single neoplastic cell and the growth kinetics in the neoplastic state have been ignored. Some researchers have discussed the impact of this assumption on their analyses, but no formal methods were available for a more rigorous application of the birth-death process. In this paper, an approximation is introduced which allows for the application of growth kinetics in the neoplastic state. The adequacy of the approximation against simulated data is evaluated and methods are developed for implementing the approximation using data on the number and size of neoplastic clones.

Animals↗
PubMed1994

Nonlinearity of dose-response functions for carcinogenicity.

Carcinogenesis data for 315 chemicals were obtained from the National Cancer Institute-National Toxicology Program (NCI-NTP) bioassay programs and were analyzed to examine the shape of carcinogenesis dose-response curves. Tumor site data were more often consistent with a quadratic response than with a linear response, suggesting that the routine use of linear dose-response models will often overestimate risk. Information from in vivo short-term mutagenicity and genotoxicity assays was also obtained for most of these rodent bioassays. It was found that there were no clear relationships between the shape of the carcinogenesis dose-response curve and the result of the short-term test. These observations argue against the concept that carcinogens that are positive in a short-term assay be regulated using a linear dose-response curve and those that are negative be regulated using a sublinear dose-response curve or a safety factor approach.

Animals↗
PubMed1994

Biostatistical issues in the design and analysis of animal carcinogenicity experiments.

Two-year animal carcinogenicity experiments are used to evaluate the potential carcinogenicity from exposure to chemicals. The choice of exposure levels, the allocation of animals to doses, the length of exposure, and the choice of interim sacrifice times all affect the power of statistical tests for carcinogenic effects and the variance of interpolated estimates of carcinogenic risk. In this paper, one aspect of this problems is considered: the ability of tumor incidence data to provide information on carcinogenic mechanism and the optimal choice of design parameters with which to achieve this purpose. The direct application of biochemical data to the estimation of carcinogenic risk is also discussed in detail.

Animals↗
PubMed1993

Receptor mechanisms and dose-response models for the effects of dioxins.

There is increasing evidence that receptor-mediated events impact one or more stages responsible for tumor development in experimental animals and humans. Although many chemicals and endogenous hormones require receptor interactions as a necessary event in their carcinogenic activity, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its structural analogs are the most visible examples of receptor-mediated carcinogens. TCDD, or dioxin as it is frequently called, interacts with the Ah receptor (AhR), which functions in a manner analogous to receptors for steroids. TCDD produces a wide spectrum of biochemical and toxic responses in in vitro and in vivo systems, and the Ah receptor is generally considered necessary for most if not all of these responses. Risk assessments for dioxin made by the United States and other countries throughout the world have been based on its carcinogenecity in experimental animals. Recently, epidemiology studies have indicated that TCDD is a human carcinogen at high doses. Because TCDD appears to be acting like a potent and persistent hormone agonist, it appears reasonable to incorporate mechanistic information on receptor-mediated events in risk assessments for TCDD. This information may be obtained from steroid receptor action and from molecular data on the Ah receptor. In this paper, we evaluate the scientific foundation on which mechanistic models for estimating dioxin's risks should be based. These models need to recognize the mechanisms possible for the diversity of biological responses that are initiated by a single receptor interacting with a single ligand. The U.S. EPA is currently reevaluating dioxin's risks by examining the possibility of developing biologically based models.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

A mechanistic model of effects of dioxin on gene expression in the rat liver.

Improved methods for estimating the shape of the response curve for effects of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are needed in order to evaluate possible adverse health effects of TCDD. A mathematical model has been constructed to describe TCDD-mediated alterations in hepatic proteins in the rat. In this model it was assumed that TCDD mediates increases in the liver concentration of transforming growth factor-alpha (TGF-alpha) by a mechanism which requires the aryl hydrocarbon (Ah) receptor. TGF-alpha subsequently binds to the epidermal growth factor (EGF) receptor, a process which is known to cause internalization of this receptor in hepatocytes. This action is thought to be an early event in the generation of a mitogenic signal. Because TCDD decreases binding of EGF in the livers of intact female rats but not in ovariectomized rats, this effect was further assumed to be dependent on estrogen action. The model postulates Ah receptor-dependent effects on the concentration of cytochrome P450 1A2 (CYP1A2), which is involved in the metabolism of estradiol, and on the concentration of the estrogen receptor. The model also incorporates information on induction of cytochrome P450 1A1 (CYP1A1) by TCDD. The biochemical response curves for all these proteins were hyperbolic (Hill exponents in the equations for their expression were found to be 1), indicating a proportional relationship between target tissue dose and protein concentration at low administered doses of TCDD. The model successfully reproduced the observed tissue distribution of TCDD, the concentrations of CYP1A1 and CYP1A2, and the effects of TCDD on the Ah, estrogen, and EGF receptors over a wide dose range.

Animals↗
PubMed1993

Effects of the mechanism of receptor-mediated gene expression on the shape of the dose-response curve.

A mathematical model of receptor-mediated gene expression that includes receptor binding of natural and xenobiotic ligands, protein synthesis and degradation, and metabolism of the xenobiotic ligand was created to identify the determinants of the shape of the dose-response profile. Values of the model's parameters were varied to reflect alternative mechanisms of expression of the protein. These assumptions had dramatic effects on the computed response to a bolus dose of the xenobiotic ligand. If all processes in the model exhibit hyperbolic kinetics, the dose-response curves can appear sigmoidal but actually be linear with a positive slope at low doses. The slope of the curve only approached zero at low dose, indicative of a threshold for response, if binding of the xenobiotic ligand to the receptor exhibited positive cooperativity (ligand binding at one site increases the affinity for ligand at another binding site on the receptor). Positive cooperativity in the rate-limiting step of protein synthesis produced dose-response curves which were "U-shaped" at low doses, also indicative of a threshold. Positive cooperativity in the metabolism of the xenobiotic ligand produced dose-response curves that increased more rapidly than linearly with increasing dose. The model illustrates the fact that response cannot be predicted from qualitative mechanistic arguments alone; any assessment of risk to health from xenobiotic chemicals must be based on a detailed quantitative examination of the kinetic behavior of each chemical species individually.

Dose-Response Relationship, Drug↗
PubMed1993

Mechanistic modelling and risk assessment.

Risk Assessment in the United States has been rapidly changing over the last few years. The historical methods and endpoints by which risk estimates were derived are gradually being replaced by newer methods and a broader spectrum of endpoints. For carcinogenic risk assessment, there is movement from the routinely used "linearized multistage model" for low dose risk estimation to methodology which is more deeply rooted in carcinogenic mechanisms and which allows the incorporation of additional data into the estimation of risks in a direct, quantitative fashion. There is also a determined effort under way to develop methods for assessing risks from exposure based on other endpoints such as effects on the immune system and the reproductive system. This paper briefly discusses some of the statistical and mathematical issues which will play important roles in determining the utility and precision of these new methods for estimating risks from environmental exposures.

Animals↗
PubMed1993

Cell proliferation and chemical carcinogenesis: symposium overview.

Cancer, by definition, is a proliferative disease. The fundamental scientific issue explored at the international symposium "Cell Proliferation and Chemical Carcinogenesis" was the impact of chemically enhanced cell proliferation on the dynamic carcinogenic processes. This conference, held at the National Institute of Environmental Health Sciences January 14-16, 1992, provided an open forum for the exchange of new results, information, and ideas in four areas: a) general principles of cell division and carcinogenesis, b) critical evaluation of cell proliferation methodologies, c) cell proliferation and modeling of organ-specific carcinogenesis, and d) cell proliferation and human carcinogenesis. This overview summarizes key findings from that symposium. The general view expressed was that although cell proliferation is involved inextricably in the development of cancers, chemically enhanced cell division does not reliably predict carcinogenicity. Our knowledge of the multistep nature of carcinogenesis has advanced substantially during recent years; however, much still needs to be learned. A greater understanding of the cellular and molecular events in chemical carcinogenesis should improve all aspects of the overall risk assessment process, including extrapolations based on dose, species, and interindividual differences.

Animals↗
PubMed1993

Using cell replication data in mathematical modeling in carcinogenesis.

Risk estimation involves the application of quantitative models of dose versus response to carcinogenicity data. Recent advances in biology, computing, and mathematics have led to the application of mathematically complicated, mechanistically based models of carcinogenesis to the estimation of risks. This paper focuses on two aspects of this application, distinguishing between models using available data and the development of new models to keep pace with research developments.

Animals↗
PubMed1993

An evaluation of some methods for fitting dose-response models to quantal-response developmental toxicology data.

The analysis of quantal-response developmental toxicology data by dose-response modeling is discussed, with emphasis on methods that avoid exact distributional assumptions. These methods (quasi-likelihood, bootstrapping, and jackknifing) are contrasted with analyses based on the beta-binomial distribution. For the resampling procedures, dose-response models are fit under a binomial likelihood. A justification for this choice of estimator in resampling plans is given, based on an extension of the standard results for asymptotic normality and consistency of maximum likelihood estimators. This justification depends only on the true distribution of the data having the usual binomial expectation. A quasi-likelihood approach is also considered, in which simple assumptions about the intralitter correlation structure are made. Quasi-likelihood methods are in theory asymptotically robust to misspecification of the intralitter correlation structure. The practical implications of these asymptotic results are evaluated in a simulation study.

Abnormalities, Drug-Induced↗