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C J Portier

Publications and source records attributed to C J Portier.

84 records · Page 5Linked to original sources
PubMed1988

An illustration of dangers of ignoring survival differences in carcinogenic data.

This paper illustrates the effects of survival differences on the routine analysis of 2-year animal carcinogenesis experiments using quantal response. Not adjusting for decreased survival in the higher dosed groups results in a decrease in the actual significance level for the quantal response trend test, and a corresponding decrease in sensitivity for detecting a true treatment effect. Similar results hold for estimation of carcinogenic risk. Tables of the range of survival differences found in recent National Toxicology Program carcinogenesis studies are presented.

Animals↗
PubMed1988

Effects of treatment-induced mortality and tumor-induced mortality on tests for carcinogenicity in small samples.

Statistical tests of carcinogenicity are shown to have varying degrees of robustness to the effects of mortality. Mortality induced by two different mechanisms is studied--mortality due to the tumor of interest, and mortality due to treatment independent of the tumor. The two most commonly used tests, the life-table test and the Cochran-Armitage linear trend test, are seen to be highly sensitive to increases in treatment lethality using small-sample simulations. Increases in tumor lethality are seen to affect the performance of commonly used prevalence tests such as logistic regression. A simple survival-adjusted quantal response test appears to be the most robust of all the procedures considered.

Animals↗
PubMed1987

Simulating failure times when the event of interest is unobservable with emphasis on animal carcinogenicity studies.

This paper discusses and summarizes the methods which can be used to simulate failure times when an intermediate event of interest is unobservable. Data from animal carcinogenicity experiments are typically of this form. The simulation of time-to-event data where cause of failure is known and the case where cause of failure is unknown are discussed. The methods proposed for simulating failure times use identifiable hazard functions and allow for random sampling of functioning experimental units at fixed times. Some useful design and programming tools are also given.

Algorithms↗
PubMed1987

Issues concerning the estimation of the TD50.

The TD50 (or tumorigenic dose rate 50) is a generally accepted measure of the carcinogenic potency of a chemical in a particular strain of animal. This paper discusses error in the estimation of the TD50 caused by intercurrent mortality and error resulting from consideration of only significant TD50's. Using computer simulations, we found that treatment-related toxicity had only a small effect on estimating the TD50, with errors seldom exceeding 5%. The TD50 is sensitive to changes in tumor lethality with errors ranging to as high as 50%. Many of these errors were significantly different from zero and the results suggest that potency estimation could be improved by basing the estimates upon the tumor incidence rate rather than upon the tumor death rate when an estimate of tumor lethality is obtainable.

Animals↗
PubMed1987

Statistical properties of a two-stage model of carcinogenesis.

Some of the statistical properties of a simple two-stage model of carcinogenesis are explored. The implications of additive treatment effects versus independent treatment effects on the shape of the dose-response curve are considered. Response that is low-dose linear results in the cases where the mutation rates are affected by dose or in the cases where treatment changes the birth rate/death rate of initiated cells in an additive fashion. Independent treatment effects lead to non-low-dose linear response when the survival of initiated cells is affected by treatment. A computer simulation experiment was performed that examined the ability of animal carcinogenesis data to differentiate between various forms of this simple two-stage model. It is shown that animal carcinogenicity experiments do not contain enough data to adequately describe the difference between these two types of effects.

Animals↗
PubMed1987

Semiparametric analysis of tumor incidence rates in survival/sacrifice experiments.

This paper addresses the problem of comparing treatment groups with respect to the rate of tumor development for animals in a survival experiment with some serial sacrifices. The analysis specifies a parametric model for the tumor incidence function, but places no parametric restrictions on the death rates. The procedure is feasible with as few as two sacrifice times and requires no individual data on cause of death. Other diseases need not act independently of the tumor of interest, nor are any restrictions imposed on tumor lethality or the relationship between the onset and death times for tumor-bearing animals. The proposed methods are illustrated with some survival/sacrifice data.

Animals↗
PubMed1986

Type 1 error and power of the linear trend test in proportions under the National Toxicology Program's modified pathology protocol.

This paper investigates the relationship between the probability of detecting a statistically significant linear trend in the proportion of animals observed to have tumors for the modified pathology protocol currently being employed by The National Toxicology Program. We considered over 300 possible dose-response relationships and tested at 5% and 1% significance levels. The results indicate that a small loss in the probability of detecting a statistically significant result will occur when the modified protocol is used instead of the previous pathology protocol. This loss varies as a function of the design of the study in terms of dose and animal allocation and as a function of the steepness of the dose-response relationship. The absolute difference between the probability of a statistically significant result for the original pathology protocol and that for the modified pathology protocol never exceeded 0.03. This difference was always less than 8% of the probability of a statistically significant result for the original pathology protocol.

Animals↗
PubMed1986

Age-specific models of mortality and tumor onset for historical control animals in the National Toxicology Program's carcinogenicity experiments.

This paper models general survival and the distribution of tumor onset times for various tumors in the data base of control animals developed by the National Toxicology Program. For general survival, a modified Weibull model is shown to give an adequate fit for both Fischer 344 rats and C57BL/6 X C3H F1, mice. In addition, data from control animals in a lifetime study of asbestos are used to support the extension of these survival curves beyond 2 years in Fischer rats. The distributions of tumor onset times are modeled using a two-parameter Weibull model. For many common tumor types, this model yielded a very good fit to the data. Finally, a summary measure of the contribution of a tumor to mortality is given.

Age Factors↗
PubMed1984

Design of animal carcinogenicity studies for goodness-of-fit of multistage models.

The effect of bioassay design changes on the variability of risk estimates in the experimental dose region is investigated. Three-dose designs with a control group and other "usual" designs utilizing 200 animals are studied in detail. Constraints on the minimum power of the linear trend test in proportions are used to eliminate designs with unacceptable power. An acceptable design region is compared to designs aimed at improving the low dose extrapolation. A group of designs acceptable for a range of objectives is proposed.

Animals↗
PubMedDate not supplied

Induction of lung lesions in female rats following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

2,3,7,8,-Tetrachlorodibenzo-p-dioxin (TCDD) has been classified as a known human carcinogen, and epidemiologic studies identify the lung as one of the target organs. Few experimental studies have attempted to characterize pulmonary effects of TCDD exposure. In this study, we characterize the induction of lesions in the lung by chronic oral TCDD exposure in diethylnitrosamine (DEN)-initiated or noninitiated female Sprague-Dawley rats. Two or 18 weeks after initiation, rats were treated with TCDD continuously for 14, 30, or 60 weeks by biweekly oral gavage (1,750 ng TCDD/kg) at a dose equivalent to 125 ng/kg body weight per day (controls received corn oil). To assess the time dependence and reversibility of potential changes, some groups included withdrawal periods of 16 or 30 weeks after 30 weeks of TCDD treatment. TCDD treatment alone for 60 weeks caused significant increases in alveolar-bronchiolar (AB) metaplasia. TCDD treatment of DEN-initiated animals for 60 weeks resulted in a significant increase in bronchiolar epithelial hyperplasia. These increases were not observed in animals treated with TCDD for 30 weeks followed by corn oil for 30 weeks, indicating that the development of these lesions required continuous exposure to TCDD. AB hyperplasia increased in an age-dependent manner after DEN initiation but was unaffected by TCDD treatment. Expression of the aromatic hydrocarbon receptor (AHR) and induction of CYP1A1 was observed only in bronchiolar Clara and ciliated cells, indicating that the mechanism of induction of AB metaplasia may be mediated by the AHR. TCDD elimination half-life was monophasic in the lung, and serum and was estimated to be 39.7 days and 44.6 days, respectively, independent of age, tissue TCDD concentration, or body weight. This is the first report to identify the AB region as a target for TCDD-induced metaplastic and proliferative changes after chronic oral exposure.

Adenoma↗