Carcinogenic Effects Of Low Doses Research Articles

Quantitative analysis of mutagenicity and carcinogenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in F344 gpt delta transgenic rats.

Quantitative analysis of the mutagenicity and carcinogenicity of the low doses of genotoxic carcinogens present in food is of pressing concern. The purpose of the present study was to determine the mutagenicity and carcinogenicity of low doses of the dietary genotoxic carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Male F344 gpt delta transgenic rats were fed diets supplemented with 0, 0.1, 1, 10 or 100 ppm IQ for 4 weeks. The frequencies of gpt transgene mutations in the liver were significantly increased in the 10 and 100 ppm groups. In addition, the mutation spectra was altered in the 1, 10 and 100 ppm groups: frequencies of G:C to T:A transversion were significantly increased in groups administered 1, 10 and 100 ppm IQ in a dose-dependent manner, and the frequencies of G:C to A:T transitions, A:T to T:A transversions and A:T to C:G transversions were significantly increased in the 100 ppm group. Increased frequencies of single base pair deletions and Spi- mutants in the liver, and an increase in glutathione S-transferase placental form (GST-P)-positive foci, a preneoplastic lesion of the liver in rats, was also observed in the 100 ppm group. In contrast, neither mutations nor mutation spectra or GST-P-positive foci were statistically altered by administration of IQ at 0.1 ppm. We estimated the point of departure for the mutagenicity and carcinogenicity of IQ using the no-observed-effect level approach and the Benchmark dose approach to characterise the dose-response relationship of low doses of IQ. Our findings demonstrate the existence of no effect levels of IQ for both in vivo mutagenicity and hepatocarcinogenicity. The findings of the present study will facilitate an understanding of the carcinogenic effects of low doses of IQ and help to determine a margin of exposure that may be useful for practical human risk assessment.

The linear no-threshold theory: Readers weigh in

The linear no-threshold theory: Readers weigh in

Low-dose radiation exposure should not be feared

Low-dose radiation exposure should not be feared

The 2007 Marie Curie prize: the linear no threshold relationship and advances in our understanding of carcinogenesis

Better knowledge of carcinogenesis has improved the assessment of the putative carcinogenic effects of low doses of Ionising Radiation (IR). Cancer induction is a main threat to multicellular organisms and safeguards have been introduced during evolution. Mutations result from endogenous agents, mainly Reactive Oxygen Species (ROS), and exogenous agents. IR and solar ultraviolet (UV) have existed since the onset of life and the existence of some congenital diseases, such as Xeroderma Pigmentosum (XP), demonstrates that without such defence mechanisms, life would have been impossible. Low doses of IR damage DNA but also activate cell defences: anti-oxidative mechanisms, DNA repair, adaptive responses, elimination of aberrant and preneoplastic cells, and immune reactions. The effectiveness of these defences decreases with the dose and is modulated by several time factors. The cell defence strategy varies with the dose, the irradiated volume and the damage inflicted on neighbouring cells. No cancer induction is detected in humans or animals for acute doses below 100 mSv. In patients treated by fractionated radiotherapy or submitted to iterative X-ray examination, the lowest dose that induces cancer appears to be at about 0.5 mSv, but doses as low as 20 mSv have a cumulative effect. Experimental studies, in vitro or on animals, suggest the existence of a threshold. In the low-dose range (< 100 mSv), epidemiological surveys do not bring any convincing data in favour of a Linear No Threshold relationship.

Arsenic in Drinking-Water and Risk for Cancer in Denmark

BackgroundArsenic is a well-known carcinogen, which is often found in drinking-water. Epidemiologic studies have shown increased cancer risks among individuals exposed to high concentrations of arsenic in drinking-water, whereas studies of the carcinogenic effect of low doses have had inconsistent results.ObjectiveOur aim was to determine if exposure to low levels of arsenic in drinking-water in Denmark is associated with an increased risk for cancer.MethodsThe study was based on a prospective Danish cohort of 57,053 persons in the Copenhagen and Aarhus areas. Cancer cases were identified in the Danish Cancer Registry, and the Danish civil registration system was used to trace and geocode residential addresses of the cohort members. We used a geographic information system to link addresses with water supply areas, then estimated individual exposure to arsenic using residential addresses back to 1970. Average exposure for the cohort ranged between 0.05 and 25.3 μg/L (mean = 1.2 μg/L). Cox’s regression models were used to analyze possible relationships between arsenic and cancer.ResultsWe found no significant association between exposure to arsenic and risk for cancers of the lung, bladder, liver, kidney, prostate, or colorectum, or melanoma skin cancer; however, the risk for non-melanoma skin cancer decreased with increasing exposure (incidence rate ratio = 0.88/μg/L average exposure; 95% confidence interval, 0.84–0.94). Results adjusted for enrollment area showed no association with non-melanoma skin cancer.ConclusionsThe results indicate that exposure to low doses of arsenic might be associated with a reduced risk for skin cancer.

Recent reports on the effect of low doses of ionizing radiation and its dose–effect relationship

Recently, the risk associated with low doses of ionizing radiation has gained new interest. Here, we analyze and discuss the major differences between two reports recently published on this issue; the report of the French Academy of Sciences and of the French Academy of Medicine published in March 2005, and the BEIR VII-Phase 2 Report of the American National Academy of Sciences published as a preliminary version in July 2005. The conclusion of the French Report is that the linear no-threshold relationship (LNT) may greatly overestimate the carcinogenic effect of low doses (<100 mSv) and even more that of very low doses (<10 mSv), such as those delivered during X-ray examinations. Conversely, the conclusion of the BEIR VII report is that LNT should be used for assessing the detrimental effects of these low and very low doses. The causes of these diverging conclusions should be carefully examined. They seem to be mostly associated with the interpretation of recent biological data. The point of view of the French Report is that these recent data are incompatible with the postulate on which LNT is implicitly based, namely the constancy of the carcinogenic effect per unit dose, irrespective of dose and dose rate.

Dose effect relationship and estimation of the carcinogenic effects of low doses of ionising radiation: the Joint Report of the Academie des Sciences (Paris) and of the Academie Nationale de Medecine

The aim of the Joint Report of the two French Academies is to discuss the validity of the linear non threshold (LNT) dose-effect relationship for assessing the detrimental effects of small doses such as those delivered by X-ray examinations (0.1 mGy to 20 mGy). The conclusion of the report is that extrapolation with LNT could greatly overestimate those risks and thus may have a detrimental effect for public health by discouraging physicians and patients from performing potentially useful radiological examinations (for example a mammography or a CT scan) when the risk appears to be too large. This conclusion against the validity of LNT is based on several types of data: 1. Epidemiology has not evidenced cancer excess in humans for doses below 100 mSv. 2. Experimental animal data have not evidenced a carcinogenic effect for doses below 100 mSv. Moreover, dose-effect relationships are very seldom linear; most of them are linear-quadratic or quadratic. A practical threshold or hormetic effects have been obser...

The carcinogenic effect of low doses: the validity of the linear no-threshold relationship

The linear no-threshold relationship (LNT) has been advocated by the International Commission on Radiological Protection (ICRP) for assessing the carcinogenic effect of low dose irradiation (below 200 mSv). Initially, the main argument of its proponents was that risks were unlikely to be underestimated with LNT. Subsequently, it has been argued that: the traversal of a cell nucleus by one track can cause a double-strand break and since the probability of disrepair is never zero there is no inferior limit to the use of LNT; the repair probability of the complex DNA lesion caused by radiation is much smaller than that of the lesion caused by cell metabolism and is not much influenced by dose and dose rate; and this relationship is compatible with epidemiological and experimental data. Gradually, what was initially an hypothesis has become a dogma. The arguments of the opponents to LNT are given. In conclusion, for doses between 200 and 20 mSv the linear extrapolation could provide the superior limit of the risk although the actual risk might be much smaller. Assessment by LNT of the carcinogenic effect for doses below 10 mSv is not scientifically justified and should be banned. Doses below 1 mSv/year should not be taken into account for risk assessment.

Modelling carcinogenic effects of low doses of inhaledradon progenies

In this study, cellular hit probabilities of alpha particlesemitted by inhaled radon progenies in sensitive epithelial cellnuclei were simulated at low exposure levels to obtain usefuldata for therejection or in support of the linear no-threshold dose-effecthypothesis. In this work, local distributions ofdeposited inhaled radon progenies in airway bifurcation modelswere computed at exposure conditions which are characteristicof homes and uranium mines. Then, maximum local depositionenhancement factors, that is, local per average depositiondensities, were simulated, and the effects of the inhomogeneityof deposition on hit probabilities were characterised. Ourresults suggest that in the vicinity of the carinal regions ofthe central airways the probability of multiple hits can bequite high even at low doses.

Modeling carcinogenic effects of low doses of inhaled radionuclides

Clinical studies have indicated that carinal regions of the airway generation 3–5 are preferential sites of tumor development following inhalation of radon progenies. These coincide with the locations where primary hot spots of deposition have been found. However, current lung dosimetry models do not take into consideration the inhomogeneity of deposition within the airways. In this study, computed local distributions of deposited inhaled radionuclides, such as radon progenies in morphologically realistic human airway bifurcation models, are analyzed for different flow rates and particle sizes. Then, local deposition enhancement factors (EF), defined as the ratio of local to average deposition densities, are computed by scanning along the surface of the bifurcation with prespecified surface area elements. The computed enhancement factors indicate that cells located at carinal ridges may receive localized doses, which are two orders of magnitude higher than the average values. Here, the probability of multiple hits can be quite high even at low doses. If the number of multiple cellular hits plays a crucial role in lung cancer development, then the maximum enhancement factor could serve as a useful parameter for a mechanism-based risk analysis of inhaled radionuclides.

Les effets cancérogènes des faibles doses de radiations

The carcinogenic effect of low doses of ionizing radiation has been a matter of much debate over the last few years. The French Academy of Science published a report on the subject in 1995. The central point of discussion concerns the validity of the linear no threshold relationship for estimating, by extrapolation, the carcinogenic effect of low doses. The aim of this article is to analyze the epidemiological data on the effect of low doses and the biological data on the mechanisms of carcinogenesis that have been obtained since 1995. These data strengthen doubts concerning the validity of current risk evaluations at low doses.

Adaptive response of human lymphocytes for the repair of radon-induced chromosomal damage

In human lymphocytes low doses of X-rays can decrease the number of chromatid deletions induced by subsequent high doses of sparsely ionizing X-rays. Because of the concern with the carcinogenic effects of low doses of α-particles from radon in homes, experiments were carried out to see if low doses of X-rays could also decrease the yield of chromosomal aberrations induced by subsequent exposure to radon. Human peripheral blood lymphocytes were irradiated with low doses of X-rays (2 cGy) at 48 h of culture, exposed to radon at 72 h of culture, and analyzed for the presence of chromatid aberrations at subsequent intervals. The frequency of chromatid aberrations induced by radon alone increased with time after exposure, indicating exaggerated differences in the stage sensitivity of cell cycle stages to high-LET radiation. Furthermore, the numbers of aberrations per cell did not follow a Poisson distribution but were over dispersed, as might be expected since high-LET radiations have a high relative biological effectiveness compared with low-LET radiations. Nevertheless, lymphocytes exposed to 2 cGy of X-rays before radon exposure contained approximately one-half the number of chromatid deletions compared with lymphocytes treated with radon alone and analzed at the same time. Thus, the putative chromosomal repair mechanism induced by low doses of sparsely ionizing radiation is also effective in reducing chromosomal aberrations induced by radon, which hitherto had been thought to be relatively independent of repair processes.

Benzene, an experimental multipotential carcinogen: results of the long-term bioassays performed at the Bologna Institute of Oncology.

In 1976, a systematic and integrated project of long-term carcinogenicity bioassays began at the Bentivoglio Experimental Unit of the Bologna Institute of Oncology. The Bologna experiments proved for the first time that benzene is an experimental carcinogen. These experiments demonstrated that benzene is carcinogenic when administered by ingestion and by inhalation and that it cause tumors in the various tested animal models (Sprague-Dawley rats, Wistar rats, Swiss mice, and RF/J mice). They also showed that benzene is a multipotential carcinogen, as it produces a variety of neoplasias in one or more of the tested animal models, including Zymbal gland carcinomas, carcinomas of the oral cavity, nasal cavities, skin, forestomach, and mammary glands, as well as angiosarcomas of the liver, hemolymphoreticular neoplasias, tumors of the lung, and possibly hepatomas. The Bologna experiments also indicated a clear-cut dose-response relationship in benzene carcinogenesis. This report presents the up-to-date results of the Bologna project. The need for more experimental research aimed at assessing the carcinogenic effects of low doses of benzene, of chemical mixtures containing benzene, and of benzene substitutes is emphasized. Also recommended are more comprehensive epidemiological investigations, extended to all types of malignancies, with particular regard to lung carcinomas.

Benzene, an Experimental Multipotential Carcinogen: Results of the Long-Term Bioassays Performed at the Bologna Institute of Oncology

In 1976, a systematic and integrated project of long-term carcinogenicity bioassays began at the Bentivoglio Experimental Unit of the Bologna Institute of Oncology. The Bologna experiments proved for the first time that benzene is an experimental carcinogen. These experiments demonstrated that benzene is carcinogenic when administered by ingestion and by inhalation and that it cause tumors in the various tested animal models (Sprague-Dawley rats, Wistar rats, Swiss mice, and RF/J mice). They also showed that benzene is a multipotential carcinogen, as it produces a variety of neoplasias in one or more of the tested animal models, including Zymbal gland carcinomas, carcinomas of the oral cavity, nasal cavities, skin, forestomach, and mammary glands, as well as angiosarcomas of the liver, hemolymphoreticular neoplasias, tumors of the lung, and possibly hepatomas. The Bologna experiments also indicated a clear-cut dose-response relationship in benzene carcinogenesis. This report presents the up-to-date results of the Bologna project. The need for more experimental research aimed at assessing the carcinogenic effects of low doses of benzene, of chemical mixtures containing benzene, and of benzene substitutes is emphasized. Also recommended are more comprehensive epidemiological investigations, extended to all types of malignancies, with particular regard to lung carcinomas.

Benzene: a multipotential carcinogen. Results of long-term bioassays performed at the Bologna Institute of Oncology.

Until recently, the incidence of benzene carcinogenicity was based only on the association between benzene occupational exposure and human leukemia, with many limited case reports and scanty epidemiological data. Available experimental studies up to 1976 on animals were rare, fragmentary, and inadequate, and had failed to prove the carcinogenic effects of benzenes. However, an integrated project of long-term carcinogenicity bioassays, begun in our laboratory in 1976 and still continuing, has shown that benzene produces a variety of tumors in rats including Zymbal gland carcinomas, carcinomas of the oral cavity, hepatocarcinomas, and possibly mammary carcinomas, lymphoreticular neoplasias, and other malignancies. Some of the tumors caused by benzene are uncommon or unusual in the breed of rats studied. Therefore benzene must be considered, under the studied experimental conditions, a strong multipotential carcinogen. The need for more experimental research is emphasized, particularly to assess the carcinogenic effects of low doses. Also recommended are more comprehensive epidemiological investigations, extended to all types of malignancies, and the application of adequate measures for primary prevention.

Carcinogenic effect of low doses of nitrosopyrrolidine administered in drinking water to Syrian golden hamsters.

Three groups of Syrian golden hamsters each consisting of 30 males and 30 females were given three different doses of nitrosopyrrolidine in their drinking water for the duration of their lives. The animals mainly showed hepatocellular neoplasms. Males were more affected than females and tumor incidence was found to be dose-dependent. No liver tumors were seen in females that received the lowest dose.