Case-control study of radon and lung cancer in New Jersey.

Radon is known to cause lung cancer in humans; however, there remain uncertainties about the effects associated with residential exposures. This case-control study of residential radon and lung cancer was conducted in five counties in New Jersey and involved 561 cases and 740 controls. A year long alpha-track detector measurement of radon was completed for approximately 93% of all residences lived in at the time of interview (a total of 2,063). While the odds ratios (ORs) for whole data were suggestive of an increased risk for exposures >75 Bq m(-3), these associations were not statistically significant. The adjusted excess OR (EOR) per 100 Bq m(-3) was -0.13 (95% CI: -0.30 to 0.44) for males, 0.29 (95% CI: -0.12 to 1.70) for females and 0.05 (95% CI: -0.14 to 0.56) for all subjects combined. An analysis of radon effects by histological type of lung cancer showed that the OR was strongest for small/oat cell carcinomas in both males and females. There was no statistical heterogeneity of radon effects by demographic factors (age at disease occurrence, education level and type of respondent). Analysis by categories of smoking status, frequency or duration did not modify the risk estimates of radon on lung cancer. The findings of this study are consistent with an earlier population-based study of radon and lung cancer among New Jersey women, and with the North American pooling of case control radon seven studies, including the previous New Jersey study. Several uncertainties regarding radon measurements and assumptions of exposure history may have resulted in underestimation of a true exposure-response relationship.

Uranium gastrointestinal absorption: the f1 factor in humans.

The present investigation was undertaken by the Department of Health, Canada, to determine the most appropriate value to use for uranium gastrointestinal absorption (f1) in setting the guideline for drinking water. Fifty participants, free from medical problems, were recruited from two communities: a rural area where drinking water, supplied from drilled wells, contained elevated levels of uranium and an urban area where the water supplied by the municipal water system contained < 1 microg l(-1). Uranium intake through food, drinking water and other beverages was monitored using the duplicate diet approach. Intake and excretion were measured by inductively coupled plasma-mass spectrometry (ICP-MS) in samples collected concurrently from the same individuals over a 3 d period. The range of f1 values was between 0.001 and 0.06, with a median of 0.009. These values were independent of gender, age, duration of exposure, daily total uranium intake and allocation of intake between food and water. Consistent with the recommendation of ICRP Publication 69, 78% were below 0.02.

The use of biologically based cancer risk models in radiation epidemiology.

Biologically based risk projection models for radiation carcinogenesis seek to describe the fundamental biological processes involved in neoplastic transformation of somatic cells into malignant cancer cells. A validated biologically based model, whose parameters have a direct biological interpretation, can also be used to extrapolate cancer risks to different exposure conditions with some confidence. In this article biologically based models for radiation carcinogenesis, including the two-stage clonal expansion (TSCE) model and its extensions, are reviewed. The biological and mathematical bases for such models are described, and the implications of key model parameters for cancer risk assessment examined. Specific applications of versions of the TSCE model to important epidemiological datasets are discussed, including the Colorado uranium miners' cohort; a cohort of Chinese tin miners; the lifespan cohort of atomic bomb survivors in Hiroshima and Nagasaki; and a cohort of over 200,000 workers included in the National Dose Registry (NDR) of Canada.

Gastrointestinal absorption of uranium in humans.

The gastrointestinal absorption factor (f1) for uranium in humans has been determined from a study of 50 volunteers, ingesting uranium at natural levels in drinking water and food. The purpose of the study was to find an appropriate f1 value for humans to use in deriving exposure guidelines for uranium. The participants ranged in age from 13 to 87 years. They were selected from two communities: New Ross, Nova Scotia with elevated uranium in drinking water, and Ottawa, Ontario with very low levels of uranium. Uranium intake and excretion were measured in samples collected concurrently from the same individuals over a three-day period. The duplicate diet method was used to monitor uranium intake in food and water. Uranium levels in all samples were measured by inductively coupled plasma mass spectrometry (ICP/MS). The distribution of f1 values obtained was non-Gaussian with a range of 0.001 to 0.06 and a median of 0.009. Seventy-eight percent of the subjects had values less than 0.02. These values are consistent with the recommendations of ICRP 69. The f1 values were not gender-sensitive and were independent of age at time of study, duration of exposure, and total uranium intake. The implications of these findings are discussed in terms of setting drinking water guidelines.

First analysis of cancer incidence and occupational radiation exposure based on the National Dose Registry of Canada.

A cohort study was conducted to investigate the relation between cancer incidence and occupational exposure to ionizing radiation. Records containing dose information from 1951 to 1988 for 191,333 persons were extracted from the National Dose Registry of Canada. The records were linked to the Canadian Cancer Data Base, with incidence data from 1969 to 1988. Standardized incidence ratios were calculated using Canadian cancer incidence rates stratified by age, sex, and calendar year. Excess relative risks were obtained from internally based dose-response analyses. The following significant results were found for males and females combined: a deficit in the standardized incidence ratio for all cancers combined; elevated standardized incidence ratios for thyroid cancer and melanoma; and elevated excess relative risks for rectum, leukemia, lung, all cancers combined, all except lung, and all except leukemia. For males, cancers of the colon, pancreas, and testis also showed significantly elevated excess relative risks. The specific cancer types listed above have been implicated in previous studies on occupational exposure to ionizing radiation, except for testis, colon, and melanoma, while the findings on thyroid cancer from previous studies are inconclusive. The thyroid standardized incidence ratios in this study are highly significant, but further investigation is needed to assess the possibility of association with occupational radiation exposure.

Characterization of uncertainty and variability in residential radon cancer risks.

Radon, a naturally occurring gas found at some level in most homes, is an established risk factor for human lung cancer. The U.S. National Research Council has recently completed a comprehensive evaluation of the health risks of residential exposure to radon and developed models for projecting radon lung cancer risks to the general population. This analysis suggests that radon may play a role in the etiology of 10-15% of all lung cancer cases in the United States, although these estimates are subject to considerable uncertainty. In this article, we present a detailed analysis of uncertainty and variability in estimates of lung cancer risk due to residential exposure to radon. We use a general framework for the analysis of uncertainty and variability that we developed previously. Specifically, we focus on estimates of the age-specific excess relative risk (ERR) and lifetime relative risk (LRR), both of which vary substantially among individuals. We also consider estimates of the population attributable risk (PAR), which reflects the proportion of the lung cancer burden attributable to radon. Variability in the ERR and LRR is largely determined by variability in residential exposure levels and in the dosimetric K-factor used to extrapolate from occupational to environmental settings. Uncertainty in the ERR and LRR is due to uncertainty in the model parameters, notably those reflecting the carcinogenic potency of radon and the modifying effect of attained age. Uncertainty in the PAR is determined by uncertainty about the values of the parameters in the risk models used to estimate the PAR. Uncertainty in radon levels in homes and the dosimetric K-factor contribute comparatively little to uncertainty in the PAR. These results suggest that reduction in uncertainty about the PAR for radon induced lung cancer can only be achieved if more reliable risk projection models can be developed.

First analysis of mortality and occupational radiation exposure based on the National Dose Registry of Canada.

A cohort mortality study of occupational radiation exposure was conducted using the records of the National Dose Registry of Canada. The cohort consisted of 206,620 individuals monitored for radiation exposure between 1951 and 1983 with mortality follow-up through December 31, 1987. A total of 5,426 deaths were identified by computerized record linkage with the Canadian Mortality Data Base. The standardized mortality ratio for all causes of death was 0.61 for both sexes combined. However, trends of increasing mortality with cumulative exposure to whole body radiation were noted for all causes of death in both males and females. In males, cancer mortality appeared to increase with cumulative exposure to radiation, without any clear relation to specific cancers. Unexplained trends of increasing mortality due to cardiovascular diseases (males and females) and accidents (males only) were also noted. The excess relative risk for both sexes, estimated to be 3.0% per 10 mSv (90% confidence interval 1.1-4.8) for all cancers combined, is within the range of risk estimates previously reported in the literature.

Chronic ingestion of uranium in drinking water: a study of kidney bioeffects in humans.

A study was conducted of the chemical effects on the human kidney induced by the chronic ingestion of uranium in drinking water. Subjects were divided into two groups: The low-exposure group, whose drinking water was obtained from a municipal water system and contained < 1 microgram uranium/L, and the high-exposure group, whose drinking water was obtained from private drilled wells and contained uranium levels that varied from 2 to 781 micrograms/L. Years of residence varied from 1 to 33 years in the low-exposure group and from 3 to 59 years in the high-exposure group. The indicators of kidney function measured in this study included glucose, creatinine, protein, and beta 2-microglobulin (BMG). The markers for cell toxicity studied were alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), and N-acetyl-beta-D-glucosaminidase (NAG). Urinary glucose was found to be significantly different and positively correlated with uranium intake for males, females, and pooled data. Increases in ALP and BMG were also observed to be correlated with uranium intake for pooled data. In contrast, the indicators for glomerular injury, creatinine and protein, were not significantly different between the two groups nor was their urinary excretion correlated to uranium intake. These results suggest that at the intakes observed in this study (0.004 microgram/kg to 9 micrograms/kg body wt), the chronic ingestion of uranium in drinking water affects kidney function and that the proximal tubule, rather than the glomerulus, is the site for this interference.

Radiocesium body burdens in residents of northern Canada from 1963-1990.

Measurements of 137Cs body burdens in over 1,100 people from five northern Canadian communities were carried out with a portable whole body counting system during the winters of 1989 and 1990. These results are compared with over 3,000 similar measurements carried out during 1967-1969. Community mean body burdens and body concentrations had decreased by approximately a factor of 30 between the two survey periods. The dependence of body concentrations on the sex and age of the subjects has also changed significantly. This can be related to changes in the patterns of caribou consumption in the northern communities. Measurements of 137Cs in urine are also available for an earlier period (1963-1966) when world-wide fallout was at its highest level. A normalization procedure was developed to calculate the average radiocesium body concentration in each community from the concentrations in urine. From data spanning a period of nearly 30 y (1963-1990), lifetime radiation doses have been estimated for most communities in the Yukon and Northwest Territories. These cumulative doses vary from 0.3 to nearly 40 mSv, with an Arctic-wide average of about 12 mSv. No health effects would be expected at these levels.

Case-control study of residential radon and lung cancer in Winnipeg, Manitoba, Canada.

A case-control study of lung cancer in relation to exposure to radon in homes in Winnipeg, Manitoba, Canada, was conducted during 1983-1990. In total, 738 individuals with histologically confirmed incident cases of lung cancer were interviewed, along with 738 controls matched on age (+/- 5 years) and sex. Radon dosimeters were placed in all residences in which the study subjects had reported living within the Winnipeg metropolitan area for at least 1 year. Radon dosimetry was done by means of integrated alpha-track measurements over a 1-year period. In the homes monitored, the average level of radon-222 was about 120 becquerels (Bq)/m3 in the bedroom area and 200 Bq/m3 in the basement. After adjusting for cigarette smoking and education, no increase in the relative risk for any of the histologic types of lung cancer observed among the cases was detected in relation to cumulative exposure to radon.

Radon, cigarette smoke, and lung cancer: a re-analysis of the Colorado Plateau uranium miners' data.

Much of our knowledge regarding the interaction of radon and tobacco smoke in the etiology of human lung cancer derives from studies of uranium miners. In this article, we present a re-analysis of lung cancer mortality in the Colorado Plateau miners' cohort within the framework of the two-mutation clonal expansion model of carcinogenesis. This analysis takes into account the patterns of exposure to radon and cigarette smoke experienced by individuals in the cohort. A simultaneous re-analysis of the British doctors' cohort indicated that those model parameters relating to the effects of tobacco were comparable in the two data sets. We found no evidence of interaction between radon and tobacco smoke with respect to their joint effect on the first or second stage mutation rates or on the rate of proliferation of initiated cells. The age-specific relative risks associated with joint exposure to radon and cigarette smoke, however, were supra-additive but submultiplicative. The analysis also confirmed that fractionation of radon exposures leads to higher lung cancer risks. Finally, we present some estimates of lung cancer risk from environmental radon exposure for non-smokers and smokers.

Dose-response relationships in carcinogenesis.

Considerable information on the carcinogenic potential of chemical and radiological agents has accumulated from the epidemiological and toxicological studies conducted to date. In this article, we discuss dose-response relationships in carcinogenesis from both empirical and theoretical points of view. Emphasis is placed on the application of biologically based models to describe observed dose-response relationships for exposure to single and multiple agents known to increase cancer risk. The implications of these observations for inferences about possible mechanisms of carcinogenesis are explored.

Additive and multiplicative relative risk in the two-stage clonal expansion model of carcinogenesis.

The effects of exposure to two carcinogens are explored within the context of the two-stage clonal expansion model of carcinogenesis. This biologically based model provides a useful framework for the quantitative description of carcinogenesis, and for defining carcinogenic agents that act as initiators, promoters, and completers. This paper addresses the combined effects of simultaneous lifetime exposure to two carcinogens as well as nonoverlapping partial lifetime exposure to each agent. Whereas the age-specific relative risk for exposure to two initiators or two completers is additive, a multiplicative relative risk model holds for exposure to an initiator and a completer, or to a promoter and a completer. Exposure to two promoters yields supra-multiplicative relative risk. Exposure to an initiator and promoter leads to multiplicative and supra-multiplicative relative risks for simultaneous lifetime and nonoverlapping partial lifetime exposures, respectively. Although departures from the additive relative risk model may thus occur at moderate to high doses, conditions are identified under which additivity will provide a good approximation to the joint risk at low doses. The methods of analysis used in this paper can also be used to determine the joint effects of exposure to two carcinogens which may affect more than one stage (initiation, promotion, completion) of the process of carcinogenesis. In general, the joint effects of exposure to such agents depends on the relative magnitude of the effects on individual stages.

On the estimation of the distribution of the latent period of multiple sclerosis.

A widely accepted hypothesis is that the initiation of multiple sclerosis occurs many years before the clinical onset of disease. Thus far, attempts to describe the characteristics of the latent period have depended entirely on ad hoc methods relying heavily on the results of migrant studies. Here, by introducing a stochastic model to describe the initiation-onset process, the distribution of the latent period is estimated, and several important consequences for multiple sclerosis discussed.