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The role of Cbfa1 genes in the progression of bone differentiation and osteogenesis was analyzed in Cbfa1-deficient mice. Southern blot analysis of the Cbfa1-mutant mice indicated the presence of inhibited osteoblast development from the mesenchyme. Mutations in the Cbfa1 gene also prevented bone formation during the early stages of ossification. On the other hand, heterozygous Cbfa1 mutant mice exhibited abnormal skeletal development that was similar to the symptoms of cleidocranial dysplasia syndrome.

The paper provides the first assessment of the occurrence of hormetic dose responses using the Comet assay, a genotoxic assay. Using a priori evaluative criteria based on the Hormetic Database on peer-reviewed comet assay experimental findings, numerous examples of hormetic dose responses were obtained. These responses occurred in a large and diverse range of cell types and for agents from a broad range of chemical classes. Limited attempts were made to estimate the frequency of hormesis within comet assay experimental studies using a priori entry and evaluative criteria, with results suggesting a frequency in the 40% range. These findings are important as they show that a wide range of genotoxic chemicals display evidence that is strongly suggestive of hormetic dose responses. These findings have significant implications for study design issues, including the number of doses selected, dose range and spacing. Likewise, the widespread occurrence of hormetic dose responses in this genotoxic assay has important risk assessment implications. [Display omitted] • Hormetic dose responses commonly occur within the Comet assay. • These findings challenge the assumption of low dose linearity for mutagens. • The findings challenge the use of the LNT for cancer risk assessment. [ABSTRACT FROM AUTHOR]

This paper reexamines the technical report (∼ one page) of Uphoff and Stern (1949) in Science that was highly relied upon by the US National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Genetics Panel to support a linearity dose response for radiation risk assessment. The present paper demonstrates that research of Uphoff and Stern (1949) to evaluate whether total dose or dose rate best estimated radiation risks included two variables, thereby precluding the ability to accurately derive a reliable conclusion about this topic. Furthermore, the acute dose selected by Uphoff and Stern was given at a strikingly low dose rate that may have precluded the capacity to adequately test the total dose/dose rate hypothesis, even with a proper study design which also this research did not possess. The issue of total dose and dose rate was much later successfully addressed by Russell et al. (1958) using a murine model, yielding a dose-rate rather than a total dose conclusion. The failure to subject the experimental details of the Uphoff and Stern (1949) study to peer-review and publication in the open literature precluded a rigorous and necessary evaluation, profoundly and improperly impacting the adoption of the linear dose response model. [Display omitted] • Key historical study for cancer risk assessment was flawed. • Historical foundations for cancer risk assessment is challenged. • Linear dose response for cancer risk was founded on a scientific error. • The historical foundations of cancer risk assessment need revision. [ABSTRACT FROM AUTHOR]

Abstract: The reported untreated mouse control data from the Oak Ridge National Laboratory assessment of dominant damage (ADD) experiments demonstrate a strong negative correlation between body weight at 4, 5, 7, 9, and 11 weeks of age and number in litter at 3 weeks of age. Independently from the above finding, mother mice are also shown to differ substantially as to the mean weights of their litters. Much literature suggests that, as a general rule, (a) heavier mice are more likely to develop spontaneous and induced tumors earlier and (b) caloric restriction decreases body weights and tumor incidences and increases longevity. The above findings make it likely that many experiments that have been interpreted to demonstrate radiation-induced transgenerational carcinogenesis have instead merely illustrated a confounding effect of extensive induced dominant lethality. That is, because of induced dominant lethality, experimental groups contain heavier mice or rats, which accordingly develop more spontaneous tumors at a faster rate than control groups, with the increased tumor rates having nothing to do with induction of dominant tumor mutations. Our findings prompt suggestions as to possible modifications in the analysis and experimental design of such experiments. [Copyright &y& Elsevier]

Germinal mosaicism is a well-established mechanism by which new spontaneous mutations enter the human population, but it is only rather recently that clusters of mutations arising in that way have been acknowledged and dealt with in specific-locus experiments on male mice. This paper reports the first cluster of germinal mosaic mutations to have been identified in experiments on the induction of dominant skeletal mutations. The mutation was detected in six offspring of a control male from the radiation part of an Assessment-of-Dominant-Damage (ADD) experiment. Reasons are provided to explain why this one litter of six mutants was excluded from the analysis of induction of dominant mutations causing the more common skeletal anomalies, which is reported in another paper. The effects of excluding this litter from that analysis are fully described. There is discussion of why such clusters should be included in some analyses but omitted in others. They should certainly always be reported because, in some cases, they can have a major impact on conclusions. Details on this one cluster of FCGM mutations provide numerous examples of how a dominant skeletal mutation that causes rare effects can also cause many of the more common anomalies. [Copyright &y& Elsevier]

Assessment-of-Dominant-Damage (ADD) experiments explored induction by proven specific-locus mutagens of dominant mutations that cause skeletal anomalies, cataracts, and stunted growth in offspring of mutagenized male mice. The data set reported here includes 6134 offspring. Mutagenic treatments included 600 R (i.e., approximately 6 Gy) of X-rays delivered in about 7 min, 600 R of gamma rays delivered over about 110 days, and four weekly intraperitoneal (i.p.) injections of 77.5 mg/kg of ethylnitrosourea (ENU). The results reported in this paper are restricted to mutations induced in stem-cell spermatogonia and to the 34 more common skeletal anomalies (i.e., those found in 0.5% or more of the control offspring). Mutation induction was demonstrated for eight anomalies in the acute X-ray experiment and for 17 anomalies (including those same eight anomalies) in the ENU experiment. In spite of the surprisingly high mutation rates found for these treatments, there was no hint of any induction of such dominant mutations by 600 R of chronic gamma radiation. Our results suggest that several anomalies related to variation in the sacralization pattern may be particularly useful for revealing induction of dominant mutations. [Copyright &y& Elsevier]