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Abstract*Correspondence, page proofs, and reprint requests to: James D. Tucker, Ph.D., Department of Biological Sciences, 1370 Biological Sciences Building, 5047 Gullen Mall, Wayne State University, Detroit, TEL: (313) 577-2783, FAX: (313) 577-3602, EMAIL: E-mail: jtucker@biology.biosci.wayne.edu. z Retired Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Chromosome translocations in peripheral blood lymphocytes of normal, healthy humans increase with age, but the effects of gender, race, and cigarette smoking on background translocation yields have not been examined systematically. Further, the shape of the relationship between age and translocation frequency (TF) has not been definitively determined. We collected existing data from sixteen laboratories in North America, Europe, and Asia on TFs measured in peripheral blood lymphocytes by fluorescence in situ hybridization whole chromosome painting among 1933 individuals. In Poisson regression models, age, ranging from newborns (cord blood) to 85 years, was strongly associated with TF and this relationship showed significant upward curvature at older ages vs. a linear relationship (p <0.001). Ever smokers had significantly higher TFs than non-smokers (rate ratio (RR) = 1.19, 95% confidence interval (CI), 1.09-1.30) and smoking modified the effect of age on TFs with a steeper age-related increase among ever smokers compared to non-smokers (p<0.001). TFs did not differ by gender. Interpreting an independent effect of race was difficult owing to laboratory variation. Our study is three times larger than any pooled effort to date, confirming a suspected curvilinear relationship of TF with age. The significant effect of cigarette smoking has not been observed with previous pooled studies of TF in humans. Our data provide stable estimates of background TF by age, gender, race, and smoking status and suggest an acceleration of chromosome damage above age 60 and among those with a history of smoking cigarettes. NIH Public Access

Although the link between high doses of ionizing radiation and damage to the heart and coronary arteries has been well established for some time, the association between lower-dose exposures and late occurring cardiovascular disease has only recently begun to emerge, and is still controversial. In this paper, we extend an earlier systematic review by Little et al. on the epidemiological evidence for associations between low and moderate doses of ionizing radiation exposure and late occurring blood circulatory system disease. Excess relative risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding and effect modification by well-known (but unobserved) risk factors, and there is statistically significant (p < 0.00001) heterogeneity between the risks. This heterogeneity is reduced, but remains significant, if adjustments are made for the effects of fractionated delivery or if there is stratification by endpoint (cardiovascular disease vs. stroke, morbidity vs. mortality). One possible biological mechanism is damage to endothelial cells and subsequent induction of an inflammatory response, although it seems unlikely that this would extend to low-dose and low-dose-rate exposure. A recent paper of Little et al. proposed an arguably more plausible mechanism for fractionated low-dose effects, based on monocyte cell killing in the intima. Although the predictions of the model are consistent with the epidemiological data, the experimental predictions made have yet to be tested. Further epidemiological and biological evidence will allow a firmer conclusion to be drawn.

Radiation-induced heritable diseases have not been demonstrated in humans and estimates of genetic risks for protection purposes are based on mouse experiments. The most comprehensive epidemiologic study is of the Japanese atomic bomb survivors and their children, which found little evidence for inherited defects attributable to parental radiation. Studies of workers exposed to occupational radiation or of populations exposed to environmental radiation appear too small and exposures too low to convincingly detect inherited genetic damage. In contrast, survivors of childhood cancer form the largest group of people exposed to high doses of ionizing radiation before reproduction and offer unique advantages for studying trans-generation effects. A wide range of gonadal doses are possible, several comparison groups are readily available (including siblings), and there is a strong willingness among cancer survivors to participate in health studies. Cancer patients also have detailed medical records that facilitate both the accurate estimation of gonadal doses and the assessment of potentially confounding factors, such as intercurrent illness, personal and family medical histories, lifestyle characteristics such as tobacco use, and circumstances at delivery. An international study is nearing completion of over 25,000 survivors of childhood cancer in the United States and Denmark who gave birth to or fathered over 6,000 children. Doses to gonads are being reconstructed from radiotherapy records with 46% over 100 mSv and 16% over 1,000 mSv. Adverse pregnancy outcomes being evaluated include major congenital malformations, cytogenetic abnormalities, stillbirths, miscarriages, neonatal deaths, total deaths, leukemia and childhood cancers, altered sex ratio, and birth weight. The main analyses are based on dose-response evaluations. Blood studies of trios (cancer survivor, spouse or partner and offspring) have been initiated to evaluate mechanistic evidence for the transmission of any radiation-induced genetic damage such as minisatellite mutations. Markers of cancer susceptibility such as chromosomal radiosensitivity and genotype profile will also be examined. In the United States series to date, 4,214 children were born to cancer survivors among whom 157 (3.7%) genetic diseases were reported in contrast to 95 (4.1%) reported conditions among 2,339 children born to sibling controls. In the Denmark series the comparable figures were 82 (6.1%) birth defects among 1,345 children of cancer survivors and 211 (5.0%) among 4,225 children of sibling controls. Coupled with prior studies, these preliminary findings, if sustained by ongoing dose-response analyses, provide reassurance that cancer treatments including radiotherapy do not carry much if any risk for inherited genetic disease in offspring conceived after exposure.