Memories of a friend and colleague - Takashi Sugimura.

Takashi Sugimura, M.D., Honorary President of the National Cancer Center in Tokyo, and former President of The Japan Academy, is regarded by many as a pre-eminent contributor to the field of environmental genotoxicology. His pioneering spirit led to many key discoveries over a long and distinguished scientific career, including the first preclinical models for gastric cancer, identification of novel mutagens from cooked food, and the development of fundamental concepts in environmental chemical carcinogenesis. With his passing on September 6, 2020, many will reflect on the loss of an astute and engaging "Scientific Giant," who with warmth and good humor maintained lasting friendships both at home and abroad, beyond his many important scientific contributions.

Estimating historic exposures at the European Gaseous Diffusion plants.

This paper describes the methods and results of an occupational exposure assessment covering 30 years of operation of the EURODIF establishment (1978-2008). The exposure assessment includes radiological, physical and chemical hazards, and takes into account of organizational changes at the establishment. Furthermore, it includes efforts to better quantify the levels of exposures using available industrial hygiene and health physics data. In total, 227 workers participated in the assessment of 26 different occupational exposures in 102 general workstations through 1978-2008. Only 7% of exposure levels were rectified by experts for internal consistency reasons. Noise, heat, trichloroethylene and soluble uranium compounds were the most prevalent exposures at the plant although their levels tended to decrease across time. Assessments of occupational exposure to noise based on JEM exposure levels were fairly well correlated with noise measurement data (Spearman's correlation coefficient, ρ=0.43) while JEM-based assessments of uranium exposure were not well correlated with uranium atmospheric measurements. This study demonstrates the importance of non-radiological exposure in the nuclear fuel industry and highlights the difficulties in managing the risks arising from these exposures. Occupational exposures remain difficult to quantify due to the scarcity of reliable monitoring data and the absence of binding occupational exposure limits for some of considered hazards.

Low dose intoxication and a crisis of regulatory models. Chemical mutagens in the Deutsche Forschungsgemeinschaft (DFG), 1963-1973.

Regulation and the prevention of danger are among the main characteristics of the modern state. However, the idea and the conceptualization of what danger is have changed over time. The genealogy of these changes shows that the history of social change and the history of knowledge are well connected. The 1970s marked the start of a social transformation of Western industrialized societies. This article proposes that this transformation was connected with basic epistemic reconfigurations and that the genealogy of risk played a significant role. This thesis is explored through the example of DFG advisory politics. Beginning in the 1960s, the DFG expert commissions that had been established to make policy and regulation recommendations began to focus more and more on the health effects of environmental pollution. The Commission for Questions of Mutagenicity played a particularly interesting role because its recommendations resulted in the foundation of a research institution run by the DFG, the Central Laboratory for Mutagenicity Testing (CML). The challenges faced by the CML in mutagenic research and testing effected a crisis of the expert-based advisory politics of the Mutagenicity Commission and a fundamental shift in the way scientific (regulatory) knowledge was perceived and valued politically. The pattern of this crisis calls to mind the constellation of the "risk society", but as will be shown, the (re)balancing of science and politics/society presented here is more adequately understood within the framework of political epistemology.

The role of the UKEMS in the development of testing guidelines.

Twenty years ago UKEMS established a sub-committee to determine the minimal professional criteria that should be achieved to comply with mutagenicity testing requirements in the UK. Recommendations on the conduct of basic and supplementary tests were published in 1983 and 1984, respectively. Despite their local distribution, these recommendations had an impact around the world. Further guidelines for statistical evaluation of mutagenicity test data and revisions to the first two volumes followed. By the early 1990s the mood was for international harmonization rather than national or regional isolation. The processes by which UKEMS had achieved its testing recommendations in the 1980s and early 1990s were successfully employed in the International Workshops for Genotoxicity Testing, of which three have now been held, and made a significant impact on OECD guidelines and ICH guidance. Summary outcomes from the latest meeting (2002 Plymouth Workshop) are given.

Achievements by CSGMT/JEMS.MMS: the Collaborative Study Group for the Micronucleus Test in the Mammalian Mutagenesis Study Group of the Environmental Mutagen Society of Japan.

The Collaborative Study Group for the Micronucleus Test (CSGMT) is one of the task groups in the Mammalian Mutagenesis Study Group (MMS) of the Environmental Mutagen Society of Japan (JEMS). It was established in 1982 and has made efforts to understand what the micronucleus test is, what are the advantages and disadvantages of the test as an in vivo detection system for mutagens/carcinogens, and to establish a standard protocol applicable to numerous chemicals. Members of the CSGMT have published more than 75 papers as part of collaborative studies and have contributed to the understanding of the nature of the micronucleus test and to setting guidelines for testing of medicinal and other chemicals. The CSGMT held some workshops to share up-to-date knowledge and techniques on the micronucleus test. Through workshops and collaborative studies, the CSGMT contributed to the maintaining of a high standard of knowledge and techniques among Japanese researchers of the micronucleus test. This paper reviews achievements made by the CSGMT until now.

From fluorescence spectra to mutational spectra, a historical overview of DNA-reactive compounds.

This historical survey has shown the emergence over a period of about 60 years of a coherent view of DNA-reactive carcinogens and their effects. The earliest workers, in the 'pre-Watson-Crick' era, probably thought that the mode of action of carcinogens, then largely comprising polycyclic aromatic hydrocarbons, would be revealed through a relationship to steroid hormones, and that they would have protein receptors. This may well apply, in a broad sense, to promoting agents in carcinogenesis. Demonstration of the mutagenicity of a chemical, mustard gas, shifted attention to alkylating agents as carcinogens, and to the concept of mutagens, carcinogens and cytotoxic agents as 'radiomimetic'. Alkylating carcinogens were shown to react with DNA in vitro and in vivo in ways consistent with their action as mutagens, particularly as inducers of base substitutions, GC-->AT transitions. Carcinogenic hydrocarbons were subsequently shown to react with DNA of their target tissue, mouse skin, to extents positively correlated with their carcinogenic potency. They were found to react through aralkylating metabolites to give products that can block DNA polymerase, but can also cause base substitutions of the transversion type, mainly GC-->TA. Current interest centres on correlating the observed base substitutions that activate oncogenes or inactivate tumour suppressor genes in human cancer with the nature of exogenous and endogenous mutagens and the chemistry of their reactions with DNA, in order to deduce whether specific carcinogens can be implicated in the etiology of cancers. Ancillary to these studies are determinations of carcinogen-DNA reaction products in DNA from human sources.