Nonlinearity of dose-response functions for carcinogenicity.

Hoel, David G.; Portier, Christopher J.

doi:10.1289/ehp.94102s1109

Cited by 41 publications

(21 citation statements)

References 28 publications

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“…In fact, examination of the shape of carcinogenesis dose-response curves of 315 chemicals tested in the National Cancer Institute-National Toxicology Program revealed that data were more often consistent with a quadratic response than with a linear response. Also, genotoxic compounds differed from linearity more often than non-genotoxic compounds (Hoel & Portier 1994).…”

Section: Discussionmentioning

confidence: 96%

A Simple Method for Quantitative Risk Assessment of Non‐Threshold Carcinogens Based on the Dose Descriptor T25

Sanner

Dybing²,

Willems

et al. 2001

Pharmacology & Toxicology

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This report provides guidance for using the dose-descriptor T25 from animal studies as a basis for quantitative risk characterisation of non-threshold carcinogens. T25 is presently used within the European Union for setting specific concentration limits for carcinogens in relation to labelling of preparations (formulations). The T25 is defined as the chronic dose rate which will give 25% of the animals tumours at a specific tissue site, after correction for spontaneous incidence, within the standard life-time of that species. The T25 is converted to the corresponding human dose descriptor, HT25, by dividing it with the appropriate scaling factor for interspecies dose scaling based on comparative metabolic rates. Subsequently, the human dose (expressed in mg per kg body-weight per day) is calculated from the available exposure data. The corresponding human life-time cancer risk is then obtained by using linear extrapolation by dividing the exposure dose with the coefficient (HT25/0.25). The results with this new method, which can easily be calculated without computer programmes, are in excellent agreement with results from computer-based extrapolation methods such as the linearised multistage model and the benchmark method using LED 10 , even though the present method only takes into consideration one single dose-response point. To overcome possible shortcomings of the present method, the estimated life-time risks are proposed to be accompanied by a commentary statement giving an overall evaluation of data that may have bearing on the carcinogenic risk and that may indicate whether the real human risk is likely to be higher or lower than the calculated life-time risk. By using the present guidance and a harmonized set of criteria and default values, the calculation of life-time cancer risk should be transparent and easy to comprehend.

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Section: Discussionmentioning

confidence: 96%

A Simple Method for Quantitative Risk Assessment of Non‐Threshold Carcinogens Based on the Dose Descriptor T25

Sanner

Dybing²,

Willems

et al. 2001

Pharmacology & Toxicology

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“…Moreover, the proportion positive only at the high dose is similar for mutagens and nonmutagens (Gold et al., unpublished data). Another analysis of the shape of dose response curves indicates that a quadratic dose response is compatible with more of the data than a linear one for both mutagens and nonmutagens (115). That mitogenesis at neartoxic doses is important in the carcinogenic response at the MTD is also suggested by the lack of chemicals that are highly carcinogenic relative to their MTD.…”

Section: Dna Repair and Other Inducible Defensesmentioning

confidence: 88%

DNA lesions, inducible DNA repair, and cell division: three key factors in mutagenesis and carcinogenesis.

Ames

Shigenaga

Gold

1993

Environ Health Perspect

268

155

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DNA lesions that escape repair have a certain probability of giving rise to mutations when the cell divides. Endogenous DNA damage is high: 106 oxidative lesions are present per rat cell. An exogenous mutagen produces an increment in lesions over the background rate of endogenous lesions. The effectiveness of a particular lesion depends on whether it is excised by a DNA repair system and the probability that it gives rise to a mutation when the cell divides. When the cell divides, an unrepaired DNA lesion has a certain probability of giving rise to a mutation. Thus, an important factor in the mutagenic effect of an exogenous agent whether it is genotoxic or non-genotoxic, is the increment it causes over the background cell division rate (mitogenesis) in cells that appear to matter most in cancer, the stem cells, which are not on their way to being discarded. Increasing their cell division rate increases mutation and therefore cancer. There is little cancer from nondividing cells. Endogenous cell division rates can be influenced by hormone levels, decreased by calorie restriction, or increased by high doses of chemicals. If both the rate of DNA lesions and cell division are increased, then there will be a multiplicative effect on mutagenesis (and carcinogenesis), for example, by high doses of a mutagen that also increases mitogenesis through cell killing. The defense system against reactive electrophilic mutagens, such as the glutathione transferases, are also almost all inducible and buffer cells against increments in active forms of chemicals that can cause DNA lesions. A variety of DNA repair defense systems, almost all inducible, buffer the cell against any increment in DNA lesions. Therefore, the effect of a particular chemical insult depends on the level of each defense, which in turn depends on the past history of exposure. Exogenous agents can influence the induction and effectiveness of these defenses. Defenses can be partially disabled by lack of particular micronutrients in the diet (e.g., antioxidants). Four endogenous processes leading to significant DNA damage are oxidation (1-3), methylation, deamination, and depurination (2). The importance of these processes is supported by the existence of specific DNA repair glycosylases for oxidative, methylated, and deaminated adducts and a repair system for apurinic sites that are produced by spontaneous depurination (3). Endogenous DNA Damage and MutagenesisDNA damage produced by oxidation appears to be the most significant endogenous damage (4). We estimate that the DNA hits per cell per day from endogenous oxidants are normally 105 in the rat and 104 in the human (5-7). These oxidative lesions are effectively but not perfectly repaired; the normal steady-state level of oxidative DNA lesions is about 106 per cell in the young rat and about twice this in the old rat (6,8). Oxidants are produced as byproducts of mitochondrial electron transport, various oxygen-utilizing enzyme system, peroxisomes, and other processes associated with normal aerobic metabolism...

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“…Without the two extreme cohorts the range becomes 0.89-2.0 with a central estimate of 1.4. No previous analysis of the epidemiological data has suggested a concave relationship, though experimental data for a wide range of carcinogens (Hoel and Portier, 1995) suggest they may be quite common. Across the range of exposures in a single study, and given the uncertainties in individual exposure estimation, a moderate degree of non-linearity will be difficult to detect.…”

Section: Lung Cancermentioning

confidence: 99%

The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure

Hodgson

Darnton

2000

The Annals of Occupational Hygiene

324

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Mortality reports on asbestos exposed cohorts which gave information on exposure levels from which (as a minimum) a cohort average cumulative exposure could be estimated were reviewed. At exposure levels seen in occupational cohorts it is concluded that the exposure specific risk of mesothelioma from the three principal commercial asbestos types is broadly in the ratio 1:100:500 for chrysotile, amosite and crocidolite respectively. For lung cancer the conclusions are less clear cut. Cohorts exposed only to crocidolite or amosite record similar exposure specific risk levels (around 5% excess lung cancer per f/ml.yr); but chrysotile exposed cohorts show a less consistent picture, with a clear discrepancy between the mortality experience of a cohort of chrysotile textile workers in Carolina and the Quebec miners cohort. Taking account of the excess risk recorded by cohorts with mixed fibre exposures (generallyϽ1%), the Carolina experience looks uptypically high. It is suggested that a best estimate lung cancer risk for chrysotile alone would be 0.1%, with a highest reasonable estimate of 0.5%. The risk differential between chrysotile and the two amphibole fibres for lung cancer is thus between 1:10 and 1:50.Examination of the inter-study dose response relationship for the amphibole fibres suggests a non-linear relationship for all three cancer endpoints (pleural and peritoneal mesotheliomas, and lung cancer). The peritoneal mesothelioma risk is proportional to the square of cumulative exposure, lung cancer risk lies between a linear and square relationship and pleural mesothelioma seems to rise less than linearly with cumulative dose. Although these non-linear relationships provide a best fit to the data, statistical and other uncertainties mean that a linear relationship remains arguable for pleural and lung tumours (but not for peritoneal tumours).Based on these considerations, and a discussion of the associated uncertainties, a series of quantified risk summary statements for different levels of cumulative exposure are presented. Crown

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Nonlinearity of dose-response functions for carcinogenicity.

Cited by 41 publications

References 28 publications

A Simple Method for Quantitative Risk Assessment of Non‐Threshold Carcinogens Based on the Dose Descriptor T25

A Simple Method for Quantitative Risk Assessment of Non‐Threshold Carcinogens Based on the Dose Descriptor T25

DNA lesions, inducible DNA repair, and cell division: three key factors in mutagenesis and carcinogenesis.

The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure

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