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Biomedical subjects

M P Little

Publications and source records attributed to M P Little.

At least 19 recordsLinked to original sources
PubMed1996

Evidence for curvilinearity in the cancer incidence dose-response in the Japanese atomic bomb survivors.

The recently released data on cancer incidence in the Japanese atomic bomb survivors are analysed using a variety of relative risk models which take account of errors in estimates of dose to assess the dose-response at low doses. For all solid cancers analysed together there is a significant positive dose-response (at the one-sided 2.5% significance level) if all survivors who received < 0.5 Sv are considered, but the significance vanishes if doses of < 0.2 Sv are considered. If a relative risk model with a threshold (the dose-response being assumed linear above the threshold) is fitted to the solid cancer data, a threshold of more than about 0.2 Sv is inconsistent with the data, whereas these data are consistent with there being no threshold. Linear-quadratic models and linear-quadratic models with an exponential cell-sterilization term provide no better fit than the linear model. For the three main radiation-inducible leukaemia subtypes analysed together (acute lymphatic leukaemia, acute myeloid leukaemia and chronic myeloid leukaemia) there is a significant positive dose-response (at the one-sided 2.5% significance level) if all survivors who received < 0.5 Sv are considered, but the significance vanishes if doses of < 0.2 Sv are considered. If a relative risk model with a threshold (the dose-response being assumed linear above the threshold) is fitted to the leukaemia data, a thresh-old of more than about 0.3 Sv is inconsistent with the data. In contrast with the solid cancer data, the best estimate for the threshold level in the leukaemia data is significantly different from zero, even when allowance is made for a possible quadratic term in the dose-response, albeit at borderline levels of statistical significance (p = 0.04). There is little evidence for curvature in the leukaemia dose-response from 0.2 Sv upwards. However, the possible underestimation of the errors in the estimates of the dose threshold as a result of confounding and uncertainties not taken into account in the analysis, together with the lack of biological plausibility of a threshold, makes the interpretation of this finding questionable.

Humans↗
PubMed1995

A review of the risks of leukemia in relation to parental pre-conception exposure to radiation.

The apparent risk of childhood leukemia resulting from paternal pre-conception radiation exposure found among children of the Sellafield (West Cumbria, UK) workforce is compared with the apparent risk in a number of other epidemiological studies. In particular, the extent of the incompatibility of the leukemia pre-conception exposure risks in the offspring of the Sellafield workforce born in the village of Seascale with the risks for those born in the rest of west Cumbria, and with the risks in the offspring of the Japanese bomb survivors, the Ontario radiation workers, and the Scottish radiation workers is discussed. A variety of animal data relating to the possibility of leukemia arising as a result of parental pre-conception exposure is also considered. It is concluded that the extent of the inconsistency of the leukemia risks in the Seascale data with this body of epidemiological and experimental data makes it highly unlikely that the association observed in the West Cumbria dataset represents a causal relationship.

Animals↗
PubMed1995

Are two mutations sufficient to cause cancer? Some generalizations of the two-mutation model of carcinogenesis of Moolgavkar, Venzon, and Knudson, and of the multistage model of Armitage and Doll.

Some generalizations of the two-mutation carcinogenesis model of Moolgavkar, Venzon, and Knudson (to allow for an arbitrary number of mutational stages) and of the multistage model of Armitage and Doll are shown to have the property that, at least in the case when the parameters of the model are eventually constant, the excess relative and absolute risks following changes in any of the parameters will eventually tend to zero. It is also shown that when the parameters governing the processes of cell division, death, or additional mutation at the penultimate stage are subject to perturbations, there are relatively large fluctuations in the hazard function for carcinogenesis for either model, which start almost as soon as the parameters are changed. For this reason it appears that without some extra stochastic "stage" appended (such as might be provided by consideration of the process of development of a malignant clone clone from a single malignant cell) the two-mutation model is not well able to describe the pattern of excess risk for solid cancers that is often seen after exposure to ionizing radiation, although leukemia may be better fitted by the two-mutation model in this respect. An examination of the results of perturbing various of the parameters for models that require three or more mutations provides indications that these models are easier to reconcile with the results from a body of epidemiological data relating to solid cancers.

Biometry↗
PubMed1992

Fitting the Armitage-Doll model to radiation-exposed cohorts and implications for population cancer risks.

The Armitage-Doll model of carcinogenesis is fitted to Japanese bomb survivors with the DS86 dosimetry and to three other radiation-exposed cohorts. The model is found to provide an adequate description of solid cancer incidence and also, to a lesser extent, of that of leukemia as a function of radiation dose when up to two radiation-affected stages are assumed. For non-leukemias the optimal model is one in which there are two radiation-affected stages separated by two additional stages. In the case of leukemia one radiation-affected stage or two adjacent stages provide suitable fits. There appear to be significant differences between the optimal models fitted to each cohort, although there is no heterogeneity within the Japanese data set by sex, by cancer type, or by age at exposure. Low-dose and low-dose-rate population risks for a population having the cancer and overall mortality rates of the current UK population are calculated on the basis of the optimal models fitted to the Japanese data to be about 8.3 x 10(-2) excess cancer deaths person-1 Sv-1, 10.1 x 10(-2) radiation-induced cancer deaths person-1 Sv-1, or 1.40 years of life lost person-1 Sv-1. Risks for a population having the mortality rates of the current Japanese population are about 6.5 x 10(-2) excess cancer deaths person-1 Sv-1, 7.8 x 10(-2) radiation-induced cancer deaths person-1 Sv-1, or 0.89 years of life lost person-1 Sv-1. It is a feature of the Armitage-Doll model, and other multistage models of carcinogenesis, that if radiation acts at more than one stage then (inverse) dose-rate effects may arise as a result of interactions between the effects of a protracted dose at the various radiation-affected stages. However, it is shown in this paper that these three measures of cancer risk in general display fairly slight dependence on administered dose in the range 0.001 to 1.0 Sv and on the length of the time over which the dose is administered in the range 1 to 100 years. Dose-rate effects resulting from the protraction of a radiation exposure over many years acting on (the same) cells at various stages of a multistep process of carcinogenesis are therefore expected to be slight. Dose-rate effects which have been observed in epidemiological studies and cellular radiobiology may thus find their explanation in other phenomena such as short-term intracellular repair.

Child↗
PubMed1991

Time variations in the risk of cancer following irradiation in childhood.

The Japanese atomic bomb survivors and three other cohorts of children exposed to radiation are analyzed, and evidence is found for a reduction in the radiation-induced relative risk of cancers other than leukemia with time following exposure. Multiplicative adjustments to the excess risk either of the form exp[-delta.(time since exposure)] or of the form [time since exposure] gamma give equivalent goodness of fit. Using the former type of adjustment an annual overall reduction of 6.9-8.6% in excess relative risk is indicated (depending on the year after which this reduction might take effect). Using the second type of multiplier an adjustment to the excess relative risk varying between [time after exposure]-2.0 and [time after exposure]-3.2 fits best overall. All these reductions are statistically significant at the 5% level. There is no significant variation by cohort, by sex, by cancer type, or by age at exposure group in the degree of annual reduction in excess relative risk. Although time-adjusted relative and absolute risk models give equivalently good fits within each cohort, there is significant variation between cohorts in the degree of increase of risk with time in the absolute risk formulation, in contrast to the lack of such heterogeneity for the relative risk formulation. It is shown that if the range of observed reductions in relative risk is assumed to operate 40 or more years after exposure in the youngest age groups, the calculated UK population risks would be reduced by 30-45% compared to those based on a constant relative risk model.

Adolescent↗
PubMed1990

Bomb survivor selection and consequences for estimates of population cancer risks.

Health records of the Japanese bomb survivor population [with the 1965 (T65D) and 1986 (DS86) dosimetry systems] have been analyzed and some evidence found for the selection effect hypothesized by Stewart and Kneale. This is found to be significant in only the first of the periods examined (1950-1958), and the effect diminishes in magnitude thereafter. There are indications that the effect might be an artifact of the T65D dosimetry, in which it is observed more strongly than in the DS86 data. There is no evidence to suggest that selection on this basis might confer correspondingly reduced susceptibility to radiation-induced cancer. If, however, one makes this assumption, as suggested by Stewart and Kneale, then current estimates of population cancer risks might need to be inflated by between 5% and 35% (for excess cancer deaths, Gy-1) or between 8% and 40% (for years of life lost, Gy-1) to account for this. It is likely that these figures, even assuming them not to be simply an artifact of the T65D dosimetry, overestimate the degree of adjustment required to the risk estimates.

Humans↗
PubMed1982

HLA type of patients with coeliac disease and malignancy in the west of Ireland.

HLA, A, B, and DR typing was done on seven of 10 patients with lymphoma, and six patients with carcinoma, all of whom had a flat small intestinal mucosa. Sixty-nine per cent (nine of 13) had HLA B8 and 71% (five of seven) had DR3. The corresponding levels for the local coeliac population are 76% and 84% respectively and the local non-coeliac population 43% and 44%. Two of the patients with lymphoma had a child with coeliac disease. The histological type of the lymphoma was malignant histiocytosis of the intestine in seven, histiocytic lymphoma in two, and was not classifiable in one. The similarity of the HLA type suggests that the flat mucosa in both groups is due to coeliac disease.

Adult↗
PubMed1978

Mucosal enzyme patterns in gastric epithelial disease.

A correlation was sought between changes in enzymes involved in gastric acid secretion (Mg-, NaK-, K- and HCO3-stimulated ATPases) and histological changes in gastric biopsies. Alkaline phosphatase was also studied. Mg- and NaK-stimulated ATPase activities increased significantly in biopsies from the pylorus and antrum which showed moderate or severe gastritis. NaK ATPase levels increased and HCO3 ATPase decreased in incisural, body and fundic mucosa which had intestinal metaplasia and atrophic gastritis. No K+ ATPase was found in normal mucosa. The total activity of alkaline phosphatase did not vary with histological changes in the gastric mucosa. Results indicate that the ATPase enzyme systems are sensitive indicators of gastric mucosal disease.

Adenosine Triphosphatases↗