A two-mutation model of carcinogenesis; application to lung tumours using rat experimental data
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Series / Report no.
Open Access
Type
Report
Language
en
Date
1998-01-31
Research Projects
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Journal Issue
Title
A two-mutation model of carcinogenesis; application
to lung tumours using rat experimental data
Translated Title
Een twee-mutatie carcinogenese model; applicatie
op longtumoren door toepassing van experimentele
rattendata
Published in
Abstract
Een twee-staps carcinogenese model werd beschouwd om de
ontwikkeling van longtumoren veroorzaakt door radon en uraniumertsstof te
beschrijven. Een tumor werd verondersteld via twee mutaties te ontstaan,
een van een normale cel naar een intermediaire cel, en een van een
intermediaire cel naar een kwaadaardige cel. De snelheid van de stappen is
afhankelijk van de mate van blootstelling aan radon en uraniumstof. Ook
werd er verondersteld dat een intermediaire cel zichzelf vermenigvuldigt
naar twee intermediaire cellen met een snelheid die afhankelijk is van de
radon en uranium concentraties. Een aantal verschillende biologisch
realistische mogelijkheden van deze afhankelijkheden werd beschouwd. Ook
werd de link tussen de aanwezigheid van tumoren en het overlijden van een
dier onderzocht. Tumoren kunnen als incidenteel, als fataal, of soms als
incidenteel en soms als fataal worden behandeld. De invloed van deze
mogelijke keuzes is hier onderzocht. Tenslotte werd er een vergelijking
gemaakt tussen een veelgebruikte benadering en de exacte oplossing van dit
model. Voor de tumorontwikkeling in de onderzochte ratten bleek dat de
snelheid van de intermediaire-malignant mutatie onafhankelijk van de
radonconcentratie was. Ook bleek dat de groei van de intermediaire cellen
groter werd bij grotere radonconcentraties. Tenslotte is gevonden dat
verschillende waarden van de modelparameters de data even goed kunnen
beschrijven maar verschillende risicoschattingen geven in andere dan de
onderzochte stralingsomstandigheden.
In this report a two stage carcinogenesis model is used to describe the development of lung tumours in rats exposed to radon and uranium ore dust. A tumour was taken to develop in two mutations steps, one from a normal cell to an intermediate cell, and one from an intermediate cell to a tumourous cell. The rates of these steps were influenced by radon and uranium dust exposure levels. Furthermore, the intermediate cell population experienced a net growth whose rate was also dependent on the radon and uranium concentrations. The relationship between mutation rate and the concentrations was investigated, and several biologically realistic possibilities were explored. The difficulties of incorporating the link between tumour incidence and death of the animal were considered. Tumours can be considered as incidental, fatal, or sometimes incidental and sometimes fatal. The effect of using these different interpretations was explored. Finally, a comparison between a much used approximation to this model, and the exact solution was made. For the tumour development in the rats examined, it was found that the normal-intermediate mutation rate is dose rate dependent, and that the intermediate-malignant mutation rate is dose rate independent. Further, it was found that the intermediate cell growth rate increases with increasing radon concentrations. Finally, it was found that different sets of parameters values are able to describe the data equally well, but give different predictions of tumour incidence for radiation exposure patterns different to those found in the data.
In this report a two stage carcinogenesis model is used to describe the development of lung tumours in rats exposed to radon and uranium ore dust. A tumour was taken to develop in two mutations steps, one from a normal cell to an intermediate cell, and one from an intermediate cell to a tumourous cell. The rates of these steps were influenced by radon and uranium dust exposure levels. Furthermore, the intermediate cell population experienced a net growth whose rate was also dependent on the radon and uranium concentrations. The relationship between mutation rate and the concentrations was investigated, and several biologically realistic possibilities were explored. The difficulties of incorporating the link between tumour incidence and death of the animal were considered. Tumours can be considered as incidental, fatal, or sometimes incidental and sometimes fatal. The effect of using these different interpretations was explored. Finally, a comparison between a much used approximation to this model, and the exact solution was made. For the tumour development in the rats examined, it was found that the normal-intermediate mutation rate is dose rate dependent, and that the intermediate-malignant mutation rate is dose rate independent. Further, it was found that the intermediate cell growth rate increases with increasing radon concentrations. Finally, it was found that different sets of parameters values are able to describe the data equally well, but give different predictions of tumour incidence for radiation exposure patterns different to those found in the data.
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