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A review of literature data regarding the heritable effects in offspring due to parents’ contact with mutagenic risk factors is presented. Studies on various factors of adverse effects on the hereditary apparatus, including chemical, infectious, physical and biological, are considered. The influence of smoking and parents’ age on the occurrence of de novo mutations is shown. Particular attention is paid to the review of publications on the role of the radiation factor in the genesis of hereditary disorders in offspring. Development stages of radiation genetics, the evolution of conception about radiation harm are described. The results of experimental, cytogenetic, molecular genetic, epidemiological studies analyzing the contribution of parental exposure to inherited pathology in progeny are presented. Special attention is paid to the “untargeted” effects of radiation and studies which prove the possibility of transgenerative transmission of genome instability are presented. The special contribution of studies on the cohort of atomic bomb victims offspring in Hiroshima and Nagasaki, which is considered as the main scientific platform for radiation risk assessment, is noted. There are articles about the offspring of persons who underwent therapeutic exposure, who had professional contact with ionizing radiation, who were exposed to radiation as a result of the Chernobyl accident, nuclear weapons tests at the Semipalatinsk test site, chronic radiation in the radioactively contaminated territory of the Techa river, areas with naturally increased radioactivity. As a result, it was noted that, despite numerous confirmations of radiation-induced effects in offspring obtained within experimental and molecular genetic studies, the results of epidemiological studies remain controversial. Possible reasons for these discrepancies are considered. An idea of views evolution regarding heritable effects in the international system of radiation safety is given. A new approach of the International Commission on Radiological Protection to heritable effects is described; the dynamics of tissue weighting factors for gonads in the assessment of effective radiation dose is shown. Methods for evaluating heritable effects are presented: the direct method and the doubling dose method. Attention is focused on the uncertainties that remain in the modern assessment of radiation genetic damage. The necessity of further study of radiation-induced heritable effects is shown. The perspective directions of studying the heritable effects are considered. The possibility of the analysis of heritable effects is described using the example of a cohort of the Mayak Production Association workers’ offspring – the country’s first nuclear industry enterprise.

A growing number of known species possess a remarkable characteristic – extreme resistance to the effects of ionizing radiation (IR). This review examines our current understanding of how organisms can adapt to and survive exposure to IR, one of the most toxic stressors known. The study of natural extremophiles such as Deinococcus radiodurans has revealed much. However, the evolution of Deinococcus was not driven by IR. Another approach, pioneered by Evelyn Witkin in 1946, is to utilize experimental evolution. Contributions to the IR-resistance phenotype affect multiple aspects of cell physiology, including DNA repair, removal of reactive oxygen species, the structure and packaging of DNA and the cell itself, and repair of iron-sulfur centers. Based on progress to date, we overview the diversity of mechanisms that can contribute to biological IR resistance arising as a result of either natural or experimental evolution.

This paper describes an episode in the life of the prominent plant radiation geneticist, Lewis J. Stadler (1897–1954) during which he became a target of the Federal Bureau of Investigation (FBI) concerning loyalty to the United States due to possible associations with the communist party. The research is based on considerable private correspondence of Dr. Stadler, the FBI interrogatory questions and Dr. Stadler’s answers and letters of support for Dr. Stadler by leading scientists such as, Hermann J. Muller.

Purpose: To review the history of radiation effects in germ cells and to attempt to discern future directions.Materials and methods: Review of published papers.Results: Recent mouse studies using m...

Ionizing radiation (IR) is environmentally prevalent and, depending on dose and linear energy transfer (LET), can elicit serious health effects by damaging DNA. Relative to low LET photon radiation (X-rays, gamma rays), higher LET particle radiation produces more disease causing, complex DNA damage that is substantially more challenging to resolve quickly or accurately. Despite the majority of human lifetime IR exposure involving long-term, repetitive, low doses of high LET alpha particles (e.g. radon gas inhalation), technological limitations to deliver alpha particles in the laboratory conveniently, repeatedly, over a prolonged period, in low doses and in an affordable, high-throughput manner have constrained DNA damage and repair research on this topic. To resolve this, we developed an inexpensive, high capacity, 96-well plate-compatible alpha particle irradiator capable of delivering adjustable, low mGy/s particle radiation doses in multiple model systems and on the benchtop of a standard laboratory. The system enables monitoring alpha particle effects on DNA damage repair and signalling, genome stability pathways, oxidative stress, cell cycle phase distribution, cell viability and clonogenic survival using numerous microscopy-based and physical techniques. Most importantly, this method is foundational for high-throughput genetic screening and small molecule testing in mammalian and yeast cells.

This systematic review evaluates the completeness of dosimetric features and their inclusion as covariates in genetic-toxicity association studies.Original research studies associating genetic features and normal tissue complications following radiotherapy were identified from PubMed. The use of dosimetric data was determined by mining the statement of prescription dose, dose fractionation, target volume selection or arrangement and dose distribution. The consideration of the dosimetric data as covariates was based on the statement mentioned in the statistical analysis section. The significance of these covariates was extracted from the results section. Descriptive analyses were performed to determine their completeness and inclusion as covariates.A total of 174 studies were found to satisfy the inclusion criteria. Studies published ≥2010 showed increased use of dose distribution information (p = 0.07). 33% of studies did not include any dose features in the analysis of gene-toxicity associations. Only 29% included dose distribution features as covariates and reported the results. 59% of studies which included dose distribution features found significant associations to toxicity.A large proportion of studies on the correlation of genetic markers with radiotherapy-related side effects considered no dosimetric parameters. Significance of dose distribution features was found in more than half of the studies including these features, emphasizing their importance. Completeness of radiation-specific clinical data may have increased in recent years which may improve gene-toxicity association studies.

This article traces disagreements about the genetic effects of low-dose radiation exposure as waged by James Neel (1915-2000), a central figure in radiation studies of Japanese populations after World War II, and Yuri Dubrova (1955-), who analyzed the 1986 Chernobyl nuclear power plant accident. In a 1996 article in Nature, Dubrova reported a statistically significant increase in the minisatellite (junk) DNA mutation rate in the children of parents who received a high dose of radiation from the Chernobyl accident, contradicting studies that found no significant inherited genetic effects among offspring of Japanese A-bomb survivors. Neel's subsequent defense of his large-scale longitudinal studies of the genetic effects of ionizing radiation consolidated current scientific understandings of low-dose ionizing radiation. The article seeks to explain how the Hiroshima/Nagasaki data remain hegemonic in radiation studies, contextualizing the debate with attention to the perceived inferiority of Soviet genetic science during the Cold War.

This paper extends a series of historical papers which demonstrated that the linear-no-threshold (LNT) model for cancer risk assessment was founded on ideological-based scientific deceptions by key radiation genetics leaders. Based on an assessment of recently uncovered personal correspondence, it is shown that some members of the United States (US) National Academy of Sciences (NAS) Biological Effects of Atomic Radiation I (BEAR I) Genetics Panel were motivated by self-interest to exaggerate risks to promote their science and personal/professional agenda. Such activities have profound implications for public policy and may have had a significant impact on the adoption of the LNT model for cancer risk assessment.

The linear non-threshold (LNT) dose response model for cancer risk assessment has been a controversial concept since its initial proposal during the 1930s. It was long advocated by the radiation genetics community in the 1950s, some two decades prior to being generally adopted within the chemical toxicology community. This paper explores possible reasons for such major differences in the acceptance of LNT for cancer risk assessment by these two key groups of scientists.

H. J. Muller is best known for his Nobel Prize work on the induction of mutations by ionizing radiation. Geneticists are less familiar with his contributions to mutation and how he related the process of mutagenesis to the gene and distinguished gene mutations from other genetic and epigenetic events such as polyploidy, chromosome rearrangements, and position effects. The hallmark of Muller's contributions is his design of genetic stocks to solve genetic problems and allow experimentation to reveal new phenomena. In this review I relate Muller's personality to his teaching and research and present a history of Muller's ideas on mutation from his first days in Morgan's fly lab to his final thoughts on what became called "Muller's ratchet", a term he did not get to enjoy because it was coined seven years after his death.

Adaptive dynamics formalism demonstrates that, in a constant environment, a continuous trait may first converge to a singular point followed by spontaneous transition from a unimodal trait distribution into a bimodal one, which is called “evolutionary branching.” Most previous analyses of evolutionary branching have been conducted in an infinitely large population. Here, we study the effect of stochasticity caused by the finiteness of the population size on evolutionary branching. By analyzing the dynamics of trait variance, we obtain the condition for evolutionary branching as the one under which trait variance explodes. Genetic drift reduces the trait variance and causes stochastic fluctuation. In a very small population, evolutionary branching does not occur. In larger populations, evolutionary branching may occur, but it occurs in two different manners: in deterministic branching, branching occurs quickly when the population reaches the singular point, while in stochastic branching, the population stays at singularity for a period before branching out. The conditions for these cases and the mean branching-out times are calculated in terms of population size, mutational effects, and selection intensity and are confirmed by direct computer simulations of the individual-based model.

The National Radiological Protection Board has recently carried out a reappraisal of the annual genetically significant dose (GSD) to the population of Great Britain arising from the practice of diagnostic radiology. The current value of 120 muGy (12 mrad) is indistinguishable from the value determined 20 years ago despite a 48% increase in the number of X-ray examinations performed per head of the population. This is mostly due to a large decrease in the contribution from obstetric radiology and to a marked reduction in the gonadal doses delivered to children for nearly all types of examination. The GSD and the frequency of X-ray examinations in Great Britain would appear to be considerably lower than those found in other industrialized countries and seem unlikely to result in more than 100 cases of serious hereditary ill-health per year at genetic equilibrium. On the other hand, diagnostic radiology is responsible for 87% of the GSD from all man-made sources of population exposure in Great Britain and there is evidence from the data collected for this reappraisal that radiological protection measures could be improved so as to reduce significantly this large contribution without detriment to patient care.

This paper explores the nature of scientific research and innovation at the intersection of technological systems via a study of atomic age plant breeding. I show how the well-established framework of “large technological systems” can be deployed to understand research dynamics in the Cold War life sciences, and further suggest that this framework might be useful in understanding still other areas of scientific research. I argue that the development of experimental tools and research programs dedicated to plant breeding via nuclear-derived technologies arose where researchers experienced the imperatives of innovation within two technological systems—nuclear and agricultural—simultaneously. In the absence of a significant infrastructure for nuclear agriculture, it was the mobility of innovations, the exchange of research tools and practices across experimental settings and research domains, which enabled nuclear-aided plant breeding to flourish for a time. As I show, understanding the dynamics of the technological systems in which researchers were embedded, including their interactions with other systems, is essential to understanding this unlikely area of research inquiry, the novel tools it relied upon, and the unusual scientific careers to which it gave rise.

This paper reassessed studies conducted under the leadership of Drosophila geneticist Curt Stern which played a pivotal role in the acceptance of the linear dose-response model by the U.S. National Academy of Sciences Biological Effects of Atomic Radiation (BEAR) I Committee and the subsequent generalization of their recommendations on the linearity dose-response paradigm for ionizing radiation and chemically induced cancer. The analysis finds serious concerns and flaws in important aspects of these experiments, their assessment, and interpretation. Of particular concern was the failure of Stern’s group to provide the necessary and promised experimental documentation to support the findings of three critical summarized experiments published as a brief technical note in Science. While this analysis questions the validity of the reported findings and their interpretations, it raises an even more serious concern about the process by which leaders in the radiation genetics community accepted such findings without requiring the necessary documentation and then used this information to support the acceptance of the linear dose-response in public policy matters as affected by risk assessment practices that have continued to the present. Environ. Mol. Mutagen. :000–000, 2011. V V C 2011 Wiley-Liss, Inc.

Although no statistically significant hereditary effects have yet been detected in the children of survivors from the atomic bombings in Hiroshima and Nagasaki, recent animal studies have found that exposure to ionizing radiation can cause genomic and epigenomic instability in the exposed individuals, as well as their offspring, and therefore, may have much larger genetic effects than predicted by earlier studies. When individuals are exposed to various environmental insults, including radiation, individual sensitivity to the insults often varies. Variance in germ-line response to radiation among individuals has been widely recognized, but it is difficult to address due to the use of inbred strains and the limited number of offspring that can be produced by a pair of mice, the common model used to study genetic effects of radiation. Herein is the first study to examine individual family responses to ionizing radiation using a parent-pedigree approach in an outbred strain of a vertebrate model, the Japanese medaka fish. Changes in frequencies of radiation-induced germline mutations at nine microsatellite loci were examined in the same families before and after exposure to one of four acute doses of ionizing radiation (0.1, 0.5, 2.5, 5 Gy, plus sham-exposed controls). Families varied significantly in pre-exposure mutation frequencies and responses to irradiation, but germline mutations were elevated in at least one family after 0.1, 0.5, and 5 Gy exposures. Variance among individuals in sensitivity to radiation is well documented for many endpoints, and our work now extends these endpoints to include germ-line mutations. Further studies are needed to elucidate dose response, effects at varying stages of spermatogenesis, and the mechanisms underlying the variance in these individual responses to radiation.

New data and historical evidence from our own and other laboratories are summarized and discussed bearing on several issues relating to mechanisms and processes involved in the formation of chromosomal aberrations following exposure to ionizing radiations. Specifically addressed are: (1) the lesions and processes affecting the appearance of chromatid-type and/or chromosome-type aberrations after radiation, (2) DNA double strand break rejoining processes and the restitution of breaks vs. the formation of exchanges, (3) the role of homologous recombinational repair in protecting cells from induction of chromatid-type aberrations after irradiation of late S/G2 cells, (4) the role of interphase chromatin structure and nuclear organization in aberration induction, (5) cellular responses for aberration induction in relation to their tissue context, and (6) approaches to the detection of aberrations previously known as "cryptic".

The results of radiation genetics studies are reviewed. The first series of studies concerned the role of heterogeneity of the human population for radiosensitivity of chromosomes in determining the pattern of dose-response relationships; correctness of extrapolation of averaged experimental data to low doses was demonstrated. In the second series of experiments, the radiation-induced adaptive response and the contribution of different factors, including genetic ones, to its formation in human cells were studied. A conclusion was made about impossibility of extrapolating data obtained for cell cultures to an organism as a whole or to a population. The third part of the study was of applied character: cytogenetic methods of biological dosimetry were used to estimate the doses of internal and external irradiation of children living on the territory of the Bryansk oblast contaminated after the Chernobyl accident. The results are discussed in the context of the present-day concepts of genetic control of sensitivity to environmental factors.

Molecular radiation biology has become a powerful discipline and tool for detailed investigations into biological mechanisms of problems and aspects of modern radiation oncology. In this context special emphasis is given to the mechanisms of DNA-repair and their relevance for radiation therapy, to the relevance of radiation-induced signal transduction for normal and tumour cell response, to the role of the micro-environment for the modification of tumour as well as normal tissue responses to radiation, and last but not the least to the aspects of individualization and molecular targeting in radiation therapy. These topics were extensively discussed during the 11th International Wolfsberg Meeting on Molecular Radiation Biology/Oncology, which was held at the Wolfsberg Conference Center in Ermatingen, Switzerland, from June 27 to 29, 2009. About 160 basic, preclinical and clinical scientists from 21 countries worldwide participated in this 2009-edition of the Wolfsberg Meeting Series on Molecular Radiation Biology/Oncology to discuss cutting-edge research in the above-mentioned topics. In the following some of the major achievements, which have been made over the recent years in the fields of basic and clinically oriented research in radiation biology as well as experimental and translational radiation oncology will be reviewed.

Short-awned (breviaristatum) mutants were induced in the barley varieties Bonus, Foma and Kristina by ionizing radiations (X- and γ-rays, neutrons) and by chemical mutagens (chiefly sulfonates and ethyleneimine) About 260 mutants were isolated and certified in 1953–1972. Of those tested for allelism approximately 140 were distributed into 17 loci represented by 2 to 26 allelic mutants. Two loci have a single allele. The skew distribution of mutants at different loci is evident. Mutation rates and proportions were determined in M2 progenies during four years of screening. Chlorophyll mutations were approximately 25 times more frequent than breviaristatum types. Among the morphological mutants, erectoides, eceriferum and breviaristaturn types were approximately equally common. In general, chemical mutagens were 2–3 times more efficient than radiations in the induction of all kinds of mutation. Differences in detectability of mutant groups depending on parent variety are briefly discussed. A brief phenotypical description of the individual breviaristatum (ari) loci is given, illustrating the pleiotropic effects often found. Mutants in loci ari-a, -c, -d, -e, which have previously been placed on the chromosome map, may serve as good marker genes. Mutants of loci ari-1 and -m are of some practical interest owing to their stiff short straw and prolific spikes.

A normal chiasma count was found in first spermatocytes from one patient with the classic symptoms of the genetic disease xeroderma pigmentosum (XP). Skin fibroblasts from this patient and from a brother affected with the same disease demonstrated a decreased ability to perform DNA repair synthesis, after ultraviolet light exposure. These findings indicate that the defective enzyme in XP, probably an incision enzyme, is not involved in the process of crossing-over

A population of Drosophila melanogaster irradiated at an early larval stage in the course of more than one hundred generations with 1120 R, and its non-irradiated control population with the same isogenic background, were investigated. The frequency of the second chromosome recessive lethals as well as with their allelism and the viability of individual chromosomes when homozygous and heterozygous were analysed. In some respects considerable differences were established between the two populations. The irradiated population had a higher frequency of lethals and a different distribution of viability of homozygous, lethal-free chromosomes than the control. However, the frequency of allelism among the lethals was higher in the control population. No effects of dominance of the recessive lethals were detected in the material studied.

The distribution of chromatid-breakage points along human chromosomes was studied in lymphocytes irradiated with X-rays during the G2-period. The breakage points were found to be preferentially located in the R-bands. This has also been shown for breakage points in exchange aberrations obtained after irradiation in the G0 stage. However, chromosomes with relatively large amounts of R-band material (showing a high frequency of exchange aberrations when irradiated during the G0 stage) appeared to be underrepresented with regard to chromatid breakage points when irradiated during the G2 stage and contrariwise. A possible mechanism that would account for this inverse relationship is discussed.

Ionizing radiation is a well established carcinogen for human cells. At low doses, radiation exposure mainly results in generation of double strand breaks (DSBs). Radiation-related DSBs could be directly linked to the formation of chromosomal rearrangements as has been proven for radiation-induced thyroid tumors. Repair of DSBs presumably involves two main pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). A number of known inherited syndromes, such as ataxia telangiectasia, ataxia-telangiectasia like-disorder, radiosensitive severe combined immunodeficiency, Nijmegen breakage syndrome, and LIG4 deficiency are associated with increased radiosensitivity and/or cancer risk. Many of them are caused by mutations in DNA repair genes. Recent studies also suggest that variations in the DNA repair capacity in the general population may influence cancer susceptibility. In this paper, we summarize the current status of DNA repair proteins as potential targets for radiation-induced cancer risk. We will focus on genetic alterations in genes involved in HR- and NHEJ-mediated repair of DSBs, which could influence predisposition to radiation-related cancer and thereby explain interindividual differences in radiosensitivity or radioresistance in a general population.

In vivo exposure effects of electromagnetic fields (EMFs) on various tissues of experiment animals have been investigated. In this sense, modeling and formulation of these biological effects have been of significant importance. In this study extremely low frequency (ELF) EMFs effects on malondialdehyde (MDA) level and myeloperoxidase (MPO) activity in kidney of guinea pigs exposed to 50 Hz magnetic fields of 1 mT, 2 mT and 3 mT have been presented. It has been planned to determine whether genetic programming (GP) is appropriate to analyze and formulate these biological effects. Consequently, it has been observed that GP can be effectively used to model MDA level and MPO activity. The performances of prediction of the proposed GP formulation versus actual experimental values are found to be quite satisfactory in terms of standard deviation and correlation coefficient. It is concluded that the GP application serves to form a database for the researchers in this field, without exposing tissues to EMF and without using too many guinea pigs. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

The linear no-threshold model (LNT) was recommended in 1956, with abandonment of the traditional threshold dose-response for genetic risk assessment. Adoption of LNT by the International Commission on Radiological Protection (ICRP) became the standard for radiation regulation worldwide. The ICRP recommends a dose limit of 1 mSv/year for the public, which is too low and which terrorizes innocent people. Indeed, LNT arose mainly from the lifespan survivor study (LSS) of atomic bomb survivors. The LSS, which asserts linear dose-response and no threshold, is challenged mainly on three points. 1) Radiation doses were underestimated by half because of disregard for major residual radiation, resulting in cancer risk overestimation. 2) The dose and dose-rate effectiveness factor (DDREF) of 2 is used, but the actual DDREF is estimated as 16, resulting in cancer risk overestimation by several times. 3) Adaptive response (hormesis) is observed in leukemia and solid cancer cases, consistently contradicting the linearity of LNT. Drastic reduction of cancer risk moves the dose-response curve close to the control line, allowing the setting of a threshold. Living organisms have been evolving for 3.8 billion years under radiation exposure, naturally acquiring various defense mechanisms such as DNA repair mechanisms, apoptosis, and immune response. The failure of LNT lies in the neglect of carcinogenesis and these biological mechanisms. Obstinate application of LNT continues to cause tremendous human, social, and economic losses. The 60-year-old LNT must be rejected to establish a new scientific knowledge-based system.

The relative abilities of C57BL and 101 marrow to repopulate the hematopoietic system of lethally x-irradiated mice was determined. The disproportionately greater ability of 101 than C57BL cells to repopulate (C57BL X 101) F/sub 1/ recipients is reported, and data are given on the relative ability of marrow from other strains of mice to repopulate lethally irradiated mice. Consistent with the observation that C57BL marrow is less efficient that 101 marrow is the finding that the number of C57BL cells required to produce functioral long-terra marrow grafts was much larger than the number of 101 cells. Factors that might influence the differential in the growth ability of the two types of marrow are discussed. (H.M.G.)

Studies on the structure and behavior of radioinduced mutant strains of Hymenolepis diminuta are reviewed. The effects of radiation upon cestodes is classified as morphological, physiological, and cytological. (P.C.H.)

Ionizing radiation/Genetic risks. The 2001 report of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) on ‘Hereditary effects of radiation’ incorporates two important concepts that have emerged from advances in radiation genetics and molecular biology: (a) most radiation-induced mutations are DNA deletions, often encompassing multiple genes; however, because of structural and functional constraints, only a proportion of induced deletions may be compatible with viability and hence recoverable in the progeny and (b) viability-compatible DNA deletions induced in human germ cells are more likely to cause multi-system developmental abnormalities rather than single-gene diseases. The work reported in this paper pursues these concepts further: it examines how mechanistic insights gained from studies of repair of radiation-induced DNA double-strand breaks (DSBs) in mammalian somatic cells and from those on the origin of deletions in human genomic disorders can be extended to germ cells the aim being the development of a framework to predict regions of the human genome that may be susceptible to radiation-induced deletions. A critical analysis of the available information permits the hypothesis that in stem cell spermatogonia, most induced deletions may arise via the non-homologous end joining (NHEJ) mechanism of DSB repair whereas in irradiated oocytes, the main mechanism is likely to be non-allelic homologous recombination (NAHR) between misaligned region-specific segmental duplications that are present in the genome (NAHR is an error-prone form of homologous recombination repair). Should this hypothesis turn out to be valid, then it is possible to build on the structural and functional aspects of genomic knowledge to devise strategies to predict where in the genome deletions may be induced by radiation, their extent and their potential phenotypes.

Ultraviolet irradiation of cells can induce a state of genomic instability that can persist for several cell generations after irradiation. However, questions regarding the time course of formation, relative abundance for different types of ultraviolet radiation, and mechanism of induction of delayed mutations remain to be answered. In this paper, we have tried to address these questions using the hypoxanthine phosphoribosyl transferase (HPRT) mutation assay in V79 Chinese hamster cells irradiated with ultraviolet A or B radiation. Delayed HPRT(-) mutations, which are indications of genomic instability, were detected by incubating the cells in medium containing aminopterin, selectively killing HPRT(-) mutants, and then treating the cells with medium containing 6-thioguanine, which selectively killed non-mutant cells. Remarkably, the delayed mutation frequencies found here were much higher than reported previously using a cloning method. Cloning of cells immediately after irradiation prevents contact between individual cell clones. In contrast, with the present method, the cells are in contact and are mixed several times during the experiment. Thus the higher delayed mutation frequency measured by the present method may be explained by a bystander effect. This hypothesis is supported by an experiment with an inhibitor of gap junctional intercellular communication, which reduced the delayed mutation frequency. In conclusion, the results suggest that a bystander effect is involved in ultraviolet-radiation-induced genomic instability and that it may be mediated in part by gap junctional intercellular communication.

Over the last decade, increasing efforts have been taken to establish associations between various genetic germline alterations and risk of normal tissue complications after radiotherapy. Though the studies have been relatively small and methodologically heterogeneous, preliminary indications have been provided that single nucleotide polymorphisms in the genes TGFB1 and ATM may modulate risk of particularly late toxicity. In addition, rare ATM alterations may enhance complication susceptibility. Nevertheless, we are still far from having an exhaustive understanding of the genetics that may underlie differences in clinical normal tissue radiosensitivity. Recent technical advances and emerging insights to the structure of inter-individual genetic variation open up unprecedented opportunities to dissect the molecular and genetic basis of normal tissue radiosensitivity. However, to fully exploit these new possibilities well-planed large-scale clinical studies are mandatory. Currently, international initiatives are taken to establish the bio banks and databases needed for this task.

The recessive visible specific locus test has been widely used for many years to investigate the genetic effects of radiation in mice. We devised an electrophoretic-specific locus test so that biochemical mutations leading to alterations in the activity or amount of four enzymes and proteins, as well as charge changes could be detected. We measured the yield of recessive visible and electrophoretic mutations in the same experiment so that a direct comparison of mutation incidence could be made. Dominant visible mutations were also scored. The recessive visible specific locus response of male C3H/HeH to a fractionated dose of 3+3 Gy X-irradiation separated by 24 h was similar to that previously reported for the F1 hybrid widely used in mutagenesis studies, and other strains. The response of C3H/HeH was significantly greater for the recessive visible mutations than for the biochemical mutations, supporting the contention that the recessive visible loci are more mutable than others. Mutational analysis of some of the mutants showed that the lesions ranged from a very deletion (30% of chromosome 14 deleted) to a point mutation. The number of loci scored in the electrophoretic test has been reassessed, and it is now considered that six, not four were scored, and this has implications for the calculation of the doubling dose.

The application of FISH chromosome painting techniques, especially the recent mFISH (and its equivalents) where all 23 human chromosome pairs can be distinguished, has demonstrated that many chromosome-type structural exchanges are much more complicated (involving more “break–rejoins” and arms) than has hitherto been assumed. It is clear that we have been greatly under-estimating the damage produced in chromatin by such agents as ionising radiation. This article gives a brief historical summary of observations leading up to this conclusion, and after outlining some of the problems surrounding the formation of complex chromosomes exchanges, speculates about possible solutions currently being proposed.

Cancer patients exhibit large patient-to-patient variability in normal tissue reactions after radiotherapy. Several observations support the hypothesis that clinical normal tissue radiosensitivity is influenced by genetic factors. However, very little is known about the genetic variation possibly underlying inter-individual differences in normal tissue reactions when unselected cancer patients undergo radiotherapy. It seems reasonable to assume that clinical radiosensitivity of normal tissues should be regarded as a so-called complex trait depending on the combined effect of several different genetic alterations. Single nucleotide polymorphisms (SNPs) make up 90% of naturally occurring sequence variation in the human genome and SNPs in genes related to the biological response to ionising radiation may affect clinical radiosensitivity. Rare genetic variants could also possibly play an important role. Thus, the 'allelic architecture' underlying differences in normal tissue reactions may be rather complicated. Recent advances in high throughput genotyping and bio-informatics provide unprecedented opportunities to unravel the genetic basis of clinical normal tissue radiosensitivity. However, to achieve maximum benefit from these advances, carefully designed clinical studies with an accrual of hundreds or thousands of patients are probably needed.

This paper is a tribute to Paul Lohman at the occasion of his retirement from the position of Professor in the Medical Faculty at the Leiden University in The Netherlands and as Director of its Department of Radiation Genetics and Chemical Mutagenesis. Paul's contributions to the science of genetic toxicology are discussed in the context of more recent insights as to how mammalian cells process DNA damage, and how this may lead to cancer and, possibly, aging. Starting with his work on the characterization of UV-induced DNA repair in cultured cells from xeroderma pigmentosum patients and the development of methodology for monitoring the removal of UV-induced lesions in human cells, the concept of the key lesion is introduced. Among the myriad of DNA lesions that can be induced in DNA as a consequence of exposure to a range of natural or synthetic mutagens, key lesions are the ones responsible for subsequent adverse effects, for example, because they give rise to mutation. The development of methods using immunofluorescence microscopy to detect and identify such key lesions and quantitate them at the single cell level, is one of the highlights of Paul's career. Based on the perceived need to evaluate mutational end points in vivo in relation to specific lesions identified by his immunofluorescence methods, Paul subsequently made crucial contributions to the development of the first transgenic mouse model to measure mutations in chromosomally integrated reporter genes. In parallel to his experimental work, Paul greatly contributed to genetic toxicology at the theoretical level by his work on the development and evaluation of methods for assessment or prediction of risks of exposure to environmental mutagens. Finally, Paul has served the discipline of genetic toxicology in a more administrative role in various ways, both locally as one of the founders of the Medical Genetics Center South-West Netherlands and internationally by playing a prominent role in organizations such as ICPEMC. Here, his numerous contributions to the journal Mutation Research, both as author on many papers and as Executive Managing Editor should not go unmentioned.