Journal Issue: Dose-Response: An International Journal: Volume 12, Issue 3
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2014-30-09
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Dose-Response, vol 12, no 3, Cover
(2014-09-01)
Dose-Response, vol 12, no 3, Table of Contents
(2014-09-01)
EPIDEMIOLOGICAL EVIDENCE OF CHILDHOOD LEUKAEMIA AROUND NUCLEAR POWER PLANTS
(2014-09-01) Janiak, Marek K
THE INFLUENCE OF TRP53 IN THE DOSE RESPONSE OF RADIATIONINDUCED APOPTOSIS, DNA REPAIR AND GENOMIC STABILITY IN MURINE HAEMATOPOIETIC CELLS
(2014-09-01) Lemon, Jennifer A; Taylor, Kristina; Verdecchia, Kyle; Phan, Nghi; Boreham, Douglas R
Apoptotic and DNA damage endpoints are frequently used as surrogate markers of cancer risk, and have been well-studied in the Trp53+/- mouse model. We report the effect of differing Trp53 gene status on the dose response of ionizing radiation exposures (0.01- 2 Gy), with the unique perspective of determining if effects of gene status remain at extended time points. Here we report no difference in the dose response for radiationinduced DNA double-strand breaks in bone marrow and genomic instability (MN-RET levels) in peripheral blood, between wild-type (Trp53+/+) and heterozygous (Trp53+/-) mice. The dose response for Trp53+/+ mice showed higher initial levels of radiation-induced lymphocyte apoptosis relative to Trp53+/- between 0 and 1 Gy. Although this trend was observed up to 12 hours post-irradiation, both genotypes ultimately reached the same level of apoptosis at 14 hours, suggesting the importance of late-onset p53-independent apoptotic responses in this mouse model. Expected radiation-induced G1 cell cycle delay was observed in Trp53+/+ but not Trp53+/-. Although p53 has an important role in cancer risk, we have shown its influence on radiation dose response can be temporally variable. This research highlights the importance of caution when using haematopoietic endpoints as surrogates to extrapolate radiation-induced cancer risk estimation.
MECHANISTIC MODELS FIT TO ED001 DATA ON >40,000 TROUT EXPOSED TO DIBENZO[A,L]PYRENE INDICATE MUTATIONS DO NOT DRIVE INCREASED TUMOR RISK
(2014-09-01) Bogen, Kenneth T
ED001-study data on increased liver and stomach tumor risks in >40,000 trout fed dibenzo[a,l]pyrene (DBP), one of the most potently mutagenic chemical carcinogens known, provide the greatest low-dose dose-response resolution of any experimentally induced tumor data set to date. Although multistage somatic mutation/clonal-expansion cancer theory predicts that genotoxic carcinogens increase tumor risk in linear no-threshold proportion to dose at low doses, ED001 tumor data curiously exhibit substantial low-dose nonlinearity. To explore the role that nongenotoxic mechanisms may have played to yield such nonlinearity, the liver and stomach tumor data sets were each fit by two models that each assume a genotoxic and a nongenotoxic pathway to increased tumor risk: the stochastic 2- stage (MVK) cancer model, and a model implementing the more recent dysregulated adaptive hyperplasia (DAH) theory of tumorigenesis. MVK and DAH fits to the data sets were each excellent, but unexpectedly each MVK fit implies that DBP acts to increase tumor risk by entirely non-mutagenic mechanisms. Given that DBP is such a potent mutagen, the MVK-model fits obtained appear to be biologically implausible, whereas the DAH-model fits reflect that model’s assumption that chemical-induced tumorigenesis typically is driven by elevated repair-cell populations rather than mutations per se.