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The Pugwash Conferences have been a highly visible attempt to create profoundly important discussions on matters related to global safety and security at the highest levels, starting in 1957 at the height of the Cold War. This paper assesses, for the first time, the formal comments offered at this first Pugwash Conference by the Nobel Prize-winning radiation geneticist, Hermann J. Muller, on the effects of ionizing radiation on the human genome. This analysis shows that the presentation by Muller was highly biased and contained scientific errors and misrepresentations of the scientific record that resulted in seriously misleading the attendees. The presentation of Muller at Pugwash served to promote, on a very visible global scale, continued misrepresentations of the state of the science and had a significant impact on policies and practices internationally and both scientific and personal belief systems concerning the effects of low dose radiation on human health. These misrepresentations would come to affect the adoption and use of nuclear technologies and the science of radiological and chemical carcinogen health risk assessment, ultimately having a profound effect on global environmental health. [ABSTRACT FROM AUTHOR]

This paper assesses the judgments of leading radiation geneticists and cancer risk assessment scientists from the mid-1950s to mid-1970s that background radiation has a significant effect on human genetic disease and cancer incidence. This assumption was adopted by the National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Genetics Panel for genetic diseases and subsequently applied to cancer risk assessment by other leading individuals/advisory groups (e.g., International Commission on Radiation Protection-ICRP). These recommendations assumed that a sizeable proportion of human mutations originated from background radiation due to cumulative exposure over prolonged reproductive periods and the linear nature of the dose-response. This paper shows that the assumption that background radiation is a significant cause of spontaneous mutation, genetic diseases, and cancer incidence is not supported by experimental and epidemiological findings, and discredits erroneous risk assessments that improperly influenced the recommendations of national and international advisory committees, risk assessment policies, and beliefs worldwide. [ABSTRACT FROM AUTHOR]

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.

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]

Purpose: The purpose of this study was the characterization of eight new dominant cataract mutations., Methods: Lenses of mutant mice were described morphologically and histologically. Each mutation was mapped by linkage studies. The candidate genes (the Cryg gene cluster and the closely linked Cryba2 gene) were sequenced., Results: Molecular analysis confirmed all mutations in Cryg genes. Five mutations lead to amino acid exchanges, two are due to premature stop codons, and one is a 10-bp deletion in the Cryge gene. Morphologically, mutant carriers expressed nonsyndromic cataracts, ranging from diffuse lenticular opacities (Crygd(ENU910) and Cryge(ENU449)), to dense nuclear and subcortical opacity (Crygd(K10), Crygc(MNU8), Cryge(Z2), Crygd(ENU4011), and Cryge(ADD15306)), to dense nuclear opacity and ruptured lenses (Cryga(ENU469)). Results of histologic analyses correlate well with the severity of lens opacity, ranging from alterations in the process of secondary fiber nucleus degradation to lens vacuoles, fiber degeneration, and disruption of the lens capsule., Conclusions: In total, 20 mutations have been described that affect the Cryg gene cluster: Nine mutations affect the Cryge gene, but only one affects the Crygb or Crygf genes. No mutation was observed in the closely linked Cryba2. Two mutations occur at the same site in the Crygd and Cryge genes (Leu45-->Pro). The unequal distribution of mutations suggests hot spots in the Cryg genes. The overall high number of mutations in these genes demonstrates their central role in the maintenance of lens transparency.