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H P Leenhouts

Publications and source records attributed to H P Leenhouts.

At least 19 recordsLinked to original sources
PubMed2005

Radiation risk is linear with dose at low doses.

This paper presents a brief argument, based on a mechanistic approach, to show that radiation risk is linear with radiation dose from zero dose up. Similarities in cellular effects lead to the assumption of a common mechanism and the DNA double strand break is identified as the crucial radiation-induced lesion. A cancer model extends the cellular effects to the main radiation risk providing confirmation of the dose effect for cancer at low doses.

DNA↗
PubMed2003

A contribution to the linear no-threshold discussion.

The paper approaches the linear no-threshold (LNT) hypothesis, currently used as the basis for recommendations in radiological protection, from the point of view of the radiation mechanism. All considerations of the validity of the LNT hypothesis based on experiment or epidemiology are dismissed because of the impossibility of deriving statistically significant data at very low doses. Instead, the LNT hypothesis is assessed from a consideration of the mechanism of radiation action. The DNA double-strand break is proposed to be the crucial radiation-induced molecular lesion. A trace is made using a series of correlations that link the DNA double-strand break to effects at the cellular level and these cellular effects are linked to the induction of cancer. Multistep modelling of carcinogenesis is used to take the link through to a consideration of radiation risk. It is concluded that, from the point of view of radiation mechanism, at very low doses the LNT hypothesis of radiation action is valid, that is, the risk function has a positive slope from zero dose.

Cell Death↗
PubMed2002

A consistent two-mutation model of bone cancer for two data sets of radium-injected beagles.

A two-mutation carcinogenesis model has been applied to model osteosarcoma incidence in two data sets of beagles injected with 226Ra. Taking age-specific retention into account, the following results have been obtained: (1) a consistent and well-fitting solution for all age and dose groups, (2) mutation rates that are linearly dependent on dose rate, with an exponential decrease for the second mutation at high dose rates, (3) a linear-quadratic dose-effect relationship, which indicates that care should be taken when extrapolating linearly, (4) highest cumulative incidences for injection at young adult age, and highest risks for injection doses of a few kBq kg(-1) at these ages, and (5) when scaled appropriately, the beagle model compares fairly well with a description for radium dial painters, suggesting that a consistent model description of bone cancer induction in beagles and humans may be possible.

Animals↗
PubMed2002

What can we say about the dose-effect relationship at very low dose?

This paper uses a few sets of low-dose experimental radiobiological data to examine just what these data sets say with respect to the shape of the dose-effect relationship at very low doses. The examination of the data leads to the conclusion that neither experimental nor epidemiological data will ever be statistically strong enough to resolve the debate unambiguously. An alternative approach to the low-dose problem is proposed based on gaining a deeper understanding of both the mechanism of action of radiation and the cellular changes which lead to malignancy. Research spending needs to be directed to more basic investigations of radiation action and to ways by which the information from these studies can be applied to the interpretation of epidemiological data.

Animals↗
PubMed2002

The implications of re-analysing radiation-induced leukaemia in atomic bomb survivors: risks for acute and chronic exposures are different.

Implications of risk estimates, as required for practical radiation protection purposes, were explored through a preliminary re-analysis of leukaemia in the Japanese atomic bomb survivors using a biologically based cancer model. The calculations for the risks posed for contracting leukaemia pointed to important differences between low-dose-rate ('chronic') and high-dose-rate ('acute') exposures. For example, the risks caused by long-term ('chronic') exposures are calculated to be substantially lower than those for 'acute' exposures. In view of these model predictions the results of epidemiological studies are discussed.

Aged↗
PubMed2002

Implications of the analysis of epidemiological data using a two-mutation carcinogenesis model for radiation risks.

A two-mutation carcinogenesis (TMC) model is used as a bridge between cellular radiation biological effects and the incidence of cancer. This model has been applied to several sets of experimental animal and epidemiological data. In this paper the advantage of the model and the implications for radiation risks at low doses are discussed with respect to the age and dose dependence of cancer incidence and the effect of age at exposure on radiation risk; the link between the radiation effect and background cancer incidence and the transfer of radiation risk across different population groups; the implications of acute and protracted radiation exposures for risks at low doses and the dose-effect relationship for radium induced bone cancer.

Age Factors↗
PubMed2002

Lower radiation weighting factor for radon indicated in mechanistic modelling of human lung cancer.

A two-mutation carcinogenesis (TMC) model was fitted to the age-dependent lung cancer incidence in a cohort of Dutch Hodgkin patients treated with radiotherapy. Employing the results of previous TMC analyses of lung cancer due to smoking (by British doctors) and due to exposure to radon (for Colorado miners) a model fit was obtained with an estimate for the low LET radiation effect at the cellular level. This allows risk calculations for lung cancer from low LET radiation. The excess absolute risks are in tune with the values reported in the literature, the excess relative risks differ among the exposed groups. Comparing the cellular radiation coefficients for radon and for low LET radiation leads to an estimated radiation weighting factor for radon of 3 (0.1-6).

Humans↗
PubMed2002

A reanalysis of liver cancer incidence in Danish patients administered thorotrast using a two-mutation carcinogenesis model.

In recent years, a two-mutation carcinogenesis (TMC) model has been used to analyze epidemiological data and estimate the radiation risks at low doses for the organs affected. Here the TMC model was used to reanalyze the liver cancer incidence in the Danish population in general and in patients administered Thorotrast, and to estimate the radiation risks for the liver. The data for 807 patients for whom sufficient data on the injected volumes of Thorotrast were available were used in this reanalysis. These data were combined with data on liver cancer incidence in the Danish population as the baseline or background incidence. Because males and females show different baseline liver cancer incidences, separate fits were made for males and females. The fits showed that the radiation effect could be ascribed entirely to the radiation dependence of the first mutation rate of the TMC model, which was higher for females than for males. The second mutation rate was not significantly dependent on dose. The radiation risks for the liver were calculated on the basis of the model parameters. These risks for lifetime exposures are about the same for males and females and are between a factor of 2 and 10 higher than current estimates. The discrepancy between the model results and previous risk estimates probably arises because the model calculations give more complete lifetime radiation risk estimates. For short-term exposures of the liver to ionizing radiation, the maximum radiation-induced excess liver cancer risk per unit dose applies to exposures at the age of about 10; exposures at ages above 35 have a radiation effect of less than approximately 15% of this maximum.

Adolescent↗
PubMed2001

A consistent two-mutation model of lung cancer for different data sets of radon-exposed rats.

A two-mutation carcinogenesis model, formulated in terms of biologically motivated equations for mutation and expansion steps, has been applied in a mechanistic modelling of the lung cancer incidence in two large data sets of rats exposed to radon, both separately and jointly. Results indicate that (1) the equations employed are able to provide an accurate description of the separate data sets, (2) the parameters in the equations take on similar values for both data sets, and (3) it is possible to construct a consistent and well-fitting solution for the joint data set. It proved not to be necessary to take into account the effect of uranium ore dust, administered to part of the data or the different rat strains of the data sets. The joint solution provides a firm basis to investigate the effects of exposure, exposure rate and age at exposure on cumulative incidence, excess relative risk and excess absolute risk. For the same total exposure, cumulative incidence reaches a maximum for exposure rates between 1 and 10 WLM per day. The so-called inverse-exposure-rate effect acts for higher exposure rates. The influence of age at exposure, however, seems to be even more pronounced. Exposure at a young age leads to considerably higher incidences than exposure at a later age. Parameters derived in this study compare fairly well with those derived for uranium miners, suggesting that a consistent model description for the induction of lung cancer by radon in rats and humans may be possible.

Animals↗
PubMed2001

Calculation of the 1995 lung cancer incidence in The Netherlands and Sweden caused by smoking and radon: risk implications for radon.

A two-mutation carcinogenesis model was used to calculate the expected lung cancer incidence caused by both smoking and exposure to radon in two populations, i.e. those of the Netherlands and Sweden. The model parameters were taken from a previous analysis of lung cancer in smokers and uranium miners and the model was applied to the two populations taking into account the smoking habits and exposure to radon. For both countries, the smoking histories and indoor radon exposure data for the period 1910-1995 were reconstructed and used in the calculations. Compared with the number of lung cancer cases observed in 1995 among both males and females in the two countries, the calculations show that between 72% and 94% of the registered lung cancer cases may be attributable to the combined effects of radon and smoking. In the Netherlands, a portion of about 4% and in Sweden, a portion of about 20% of the lung cancer cases (at ages 0-80 years) may be attributable to radon exposure, the numbers for males being slightly lower than for females. In the Netherlands, the proportions of lung cancers attributable to smoking are 91% for males and 71% for females; in Sweden, the figures are 70% and 56%, respectively. The risk from radon exposure is dependent on gender and cigarette smoking: the excess absolute risk for continuous exposure to 100 Bq m-3 ranges between 0.003 and 0.006 and compares well with current estimates, e.g. 0.0043 of the International Commission on Radiological Protection (ICRP). The excess relative risk for continuous exposure to 100 Bq m-3 shows a larger variation, ranging generally between 0.1 for smokers and 1.0 for non-smokers. The results support the assumption that exposure to (indoor) radon, even at a level as low as background radiation, causes lung cancer proportional to the dose and is consistent with risk factors derived from the miners data.

Adult↗
PubMed2000

Analysis of thyroid cancer data from the Ukraine after 'Chernobyl' using a two-mutation carcinogenesis model.

The thyroid cancer data of children in the northern regions of the Ukraine after the reactor accident at Chernobyl were combined with thyroid dose measurements in the same regions and analysed using a two-mutation carcinogenesis model. The best fit was obtained for radiation acting as an initiating agent, i.e. on the first mutation of the model. The observed relatively high increase of thyroid cancer incidence after 1990 in children exposed to radiation released after the reactor accident could be ascribed to the high thyroid doses and the relatively low background thyroid cancer incidence in children. The maximum annual incidence is predicted to occur fairly soon after the reactor accident, i.e. about 10 years. For adults, the predicted relative increase of annual thyroid cancers is much lower than for children younger than 20 years. The modelling results are used to derive risk estimates for radiation-induced thyroid cancer. These risk estimates are dependent on age at exposure, follow-up time and the background thyroid cancer incidence. The calculated excess absolute risk for a population of all ages is about one-third of that currently used by ICRP, but for children the calculated absolute risks are about a factor of 3 higher than derived in other epidemiological studies. The model results indicate that the excess absolute radiation risk per unit dose for children is about the same as or a little lower than that for adults.

Adolescent↗
PubMed2000

Analysis of lung tumour risk in radon-exposed rats: an intercomparison of multi-step modelling.

Three carcinogenesis modelling groups have both jointly and separately applied a multi-step carcinogenesis model with clonal expansion to one data set of lung tumours in rats exposed to radon (CEA, France). This study was designed to investigate the differences in modelling approach and fitting procedures used by the three groups in detail, and to explore possible discrepancies in the results. Using the same model assumptions and a (linear) radiation dependence on the first model step only, the three groups arrived at identical best fits, proving that the mathematical formalisms and fitting procedures do not lead to different results. However, when each group was allowed to find its own preferred fit for this data set, all three found a significantly better, but different fit to the data. All solutions indicated radiation to be an initiating agent and found additional radiation action necessary. The character of this additional radiation dependence, however, could not be unambiguously pinpointed. Tumour incidence data were described equally well when radiation dependence was taken into account in clonal expansion ("promotion") or in the second mutational step ("transformation"); extension to three model stages also resulted in an adequate description. The study showed that, although the three groups used one carcinogenesis model in principle, different model assumptions and/or different methods of finding the "best fit" could result in different descriptions of experimental data. This implies that on statistical grounds, different interpretations can be given for the action that radiation had in this data set. Different data, i.e. other data sets with age-dependent tumour data and/or information from cellular radiobiology experiments, are needed to specifically pin down the radiation dependence in the multi-step carcinogenesis process.

Age Factors↗
PubMed2000

An analysis of bone and head sinus cancers in radium dial painters using a two-mutation carcinogenesis model.

Bone and head sinus cancer incidence after ingestion of 226Ra and 228Ra by radium dial painters is analysed using a two-mutation clonal expansion model for radiation carcinogenesis, taking into account the retention and radiation patterns of these nuclides in the body. The best fit is obtained for compact bone retention and efficient diffusion of 222Rn to the bone cavities and radiation action on both mutation rates of the cancer model, as found in a similar analysis of bone sarcomas after 226Ra injection in beagles. The model parameters of the best fit are consistent with cellular radiobiological data and a previous analysis of lung cancer in uranium miners. Due to the low background incidence of bone and head sinus cancer, the resulting dose-effect relationships for these cancers are linear-quadratic with radium ingestion and alpha radiation dose. These results do not support a threshold dose concept, but the risks at low doses calculated by the model come out to about a factor 10 lower than using a linear extrapolation of the data to low doses, a procedure currently applied by ICRP and EPA. Furthermore, the model results indicate radiation risks at low doses to be related with background cancer incidence between relative and absolute radiation risk projections. The results, which are dependent on the model assumptions, might be more generally applicable for bone seekers and will therefore need further study to arrive at better radiation risk estimations.

Adult↗
PubMed1999

Radon-induced lung cancer in smokers and non-smokers: risk implications using a two-mutation carcinogenesis model.

Three sets of data (population statistics in non-smokers, data from an investigation of the smoking habits of British doctors and a study of Colorado uranium miners) were used to analyse lung cancer in humans as a function of exposure to radon and smoking. One of the aims was to derive implications for radon risk estimates. The data were analysed using a two-mutation radiation carcinogenesis model and a stepwise determination of the model parameters. The basic model parameters for lung cancer were derived from the age dependence fit of the spontaneous lung cancer incidence in non-smokers. The effect of smoking was described by two additional parameters and, subsequently, the effect of radon by three other parameters; these five parameters define the dependence of the two mutation steps on smoking and exposure to radon. Using this approach, a consistent fit and comprehensive description of the three sets of data have been achieved, and the parameters could, at least partly, be related to cellular radiobiological data. The model results explain the different effect of radon on non-smokers and smokers as seen in epidemiological data. Although the analysis was only applied to a limited number of populations, lung cancer incidence as a result of radon exposure is estimated to be about ten times higher for people exposed at the age of about 15 than at about 50, although this effect is masked (especially for smokers) by the high lung cancer incidence from smoking. Using the model to calculate the lung cancer risks from lifetime exposure to radon, as is the case for indoor radon, higher risks were estimated than previously derived from epidemiological studies of the miners' data. The excess absolute risk per unit exposure of radon is about 1.7 times higher for smokers of 30 cigarettes per day than for non-smokers, even though, as a result of the low spontaneous tumour incidence in the non-smokers, the excess relative risk per unit exposure for the smokers is about 20 times lower than for the non-smokers. This prediction could have serious consequences for the transfer of risk estimates between populations. Although the solution of the model presented here is not unique but dependent on the model assumptions, the predictions and risk implications are sufficiently supported to justify a thorough investigation of the applicability of the model to other radon data sets.

Adolescent↗