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.

["The King of Diseases": the special attention that is paid to cancer patients and how it came about? An Essay]. / "Der König der Krankheiten" - Wie entstand die besondere Aufmerksamkeit für Krebskranke? Ein Essay.

The history of cancer in the 20(th) century demonstrates that various factors have contributed to the perception of cancer as the "Emperor of All Maladies" although this has never been true from an epidemiological perspective. Depending on the geographical area, infectious diseases like tuberculosis or malaria or cardiovascular diseases still head the list of the most common illnesses. Within the group of chronic degenerative diseases, however, cancer has outdistanced the widespread classic infectious diseases as a result of the epidemiologic transition in 1900, at least in the more developed countries. Under the Nazi dictatorship (from 1933 to 1945), the perception of cancer in Germany got particularly promoted for propaganda purposes. In the Atomic Era cancer attracted strong public interest as a worthwhile object of research in radiation therapies using large-scale facilities (electron accelerators, "electron guns"). A further upsurge of interest in cancer could then be witnessed in the context of the debate about the pathogenic role of environmental factors. Notably, this increased perception of cancer has not yet been significantly associated with a sweeping success in cancer treatment, but rather with ideologies, hopes and innovation impulses. (As supplied by publisher).

From pathology to chemistry and back: James W. Cook and early chemical carcinogenesis research.

During the 1920s, concerns over occupational cancers in the tar, coal-gas and synthetic dye industries stimulated investigations into the responsible carcinogenic agents. Chemical pathologist Ernest L. Kennaway and organic chemist James W. Cook at London's Cancer Hospital Research Institute were the first to identify pure carcinogenic coal-tar polyaromatic hydrocarbons. Cook, who joined Kennaway in 1929, synthesised and tested hundreds of compounds, seeking to identify the exact relationship between chemical constitution and cancer. This paper reviews Cook's research programme until the early 1940s, and the attempt of his collaborator, Cambridge biochemist Joseph Needham, to identify the biological basis of carcinogenesis. In this, they drew upon structural and functional analogies between recently discovered hormones and carcinogens. Cook established novel ways of studying chemical carcinogenesis, although conflicting empirical results and understandings of cancerous growth militated against the development of a coherent mechanistic theory.

Arsenic exposure and toxicology: a historical perspective.

The metalloid arsenic is a natural environmental contaminant to which humans are routinely exposed in food, water, air, and soil. Arsenic has a long history of use as a homicidal agent, but in the past 100 years arsenic, has been used as a pesticide, a chemotherapeutic agent and a constituent of consumer products. In some areas of the world, high levels of arsenic are naturally present in drinking water and are a toxicological concern. There are several structural forms and oxidation states of arsenic because it forms alloys with metals and covalent bonds with hydrogen, oxygen, carbon, and other elements. Environmentally relevant forms of arsenic are inorganic and organic existing in the trivalent or pentavalent state. Metabolism of arsenic, catalyzed by arsenic (+3 oxidation state) methyltransferase, is a sequential process of reduction from pentavalency to trivalency followed by oxidative methylation back to pentavalency. Trivalent arsenic is generally more toxicologically potent than pentavalent arsenic. Acute effects of arsenic range from gastrointestinal distress to death. Depending on the dose, chronic arsenic exposure may affect several major organ systems. A major concern of ingested arsenic is cancer, primarily of skin, bladder, and lung. The mode of action of arsenic for its disease endpoints is currently under study. Two key areas are the interaction of trivalent arsenicals with sulfur in proteins and the ability of arsenic to generate oxidative stress. With advances in technology and the recent development of animal models for arsenic carcinogenicity, understanding of the toxicology of arsenic will continue to improve.

Benzene-induced cancers: abridged history and occupational health impact.

Benzene-induced cancer in humans was first reported in the late 1920s. Carcinogenesis findings in animals were not reported conclusively until 1979. Industry exploited this "discrepancy" to discredit the use of animal bioassays as surrogates for human exposure experience. The cardinal reason for the delay between first recognizing leukemia in humans and sought-after neoplasia in animals centers on poor design and conduct of experimental studies. The first evidence of carcinogenicity in animals manifested as malignant tumors of the zymbal glands (sebaceous glands in the ear canal) of rats, and industry attempted to discount this as being irrelevant to humans, as this organ is vestigial and not present per se in humans. Nonetheless, shortly thereafter benzene was shown to be carcinogenic to multiple organ sites in both sexes of multiple strains and multiple species of laboratory animals exposed via various routes. This paper presents a condensed history of the benzene bioassay story with mention of benzene-associated human cancers.

History of environmental and molecular mutagenesis.

Environmental and Molecular Mutagenesis, the journal of the Environmental Mutagen Society (EMS), marks its 25th anniversary in 2004. The journal, originally called Environmental Mutagenesis, was established in 1979 with Seymour Abrahamson as its first editor. The development of the journal is closely linked to the evolution of the fields of mutation research and genetic toxicology. This perspective traces the founding of the journal and discusses its editorial history, growth, content, style, administration, and relationship to the EMS.

History of the science of mutagenesis from a personal perspective.

A career in the study of mutagenesis spanning 50 years is a gift few scientists have been bestowed. My tenure in the field started in 1953, the year the structure of DNA became known (Watson and Crick [1953]: Nature 171:737). Before that time, it was suspected that DNA was the genetic material based on the research of Oswald T. Avery (Avery et al. [1944]: J Exp Med 79:137), but many scientists still believed that proteins or polysaccharides could be the genetic material. The present article describes a lifetime of personal experience in the field of chemical mutagenesis. The methods used to treat viruses with chemical mutagens were well developed in the 1950s. Here I review the early use of nitrous acid and hydroxylamine as mutagens in eukaryotes, the development of methods for the metabolic activation of mutagens by microsomal preparations, and the selection of a mutant tester set for the qualitative characterization of the mutagenic activity of chemicals. These studies provided critical background information that was used by Bruce Ames in the development of his Salmonella/microsome assay, widely known as the Ames test (Ames et al. [1973]: Proc Nat Acad Sci USA 70:2281-2285). This article also describes how a set of diagnostic chemical mutagens was selected and used to identify the molecular nature of gene mutations. Today, DNA sequencing has replaced the use of diagnostic mutagens, but studies of this kind formed the foundation of modern mutation research. They also helped set the stage for the organization of the Environmental Mutagen Society and the Environmental Mutagen Information Center, which are described. The article ends with the development of mammalian single-cell mutation assays, the first system for studying in vivo mutagenesis using recoverable vectors in transgenic animals, other mutation assays in intact mammals, and my thoughts on the critically important area of germ cell mutagenesis. This narrative is not a complete autobiographical account, in that I have selected only those experiences that I feel are important for the history of the field and the edification of today's students. I hope I have shown that science not only is a valuable pursuit but can also be fun, stimulating, and satisfying. A good sense of humor and the knowledge that many discoveries come by serendipity are essential.

Estimating historical occupational exposure to airborne hexavalent chromium in a chromate production plant: 1940--1972.

This article presents a retrospective exposure assessment for 493 workers who were occupationally exposed to airborne hexavalent chromium, Cr(VI), at a Painesville, Ohio, chromate production plant from 1940-1972. Exposure estimates were reconstructed using a job-exposure matrix approach that related job titles with area monitoring data from 21 industrial hygiene surveys conducted from 1943 to 1971. No personal monitoring data were collected. Specifically, airborne Cr(VI) concentration profiles for 22 areas of the plant, termed job-exposure group (JEG) areas, were constructed for three distinct time periods (1940-1949, 1950-1964, and 1965-1972), with cut points based on known major plant and process changes. Average airborne Cr(VI) concentrations were the highest for the bridge crane operators (5.5 mg/m3) prior to 1965, although only four cohort members held this job title. Airborne concentrations for the rest of the production areas of the plant ranged from 1.9 mg/m3 for packers in the 1940s to 0.012 mg/m3 for ore mill operators after 1964. For nearly all JEG areas, exposures decreased over time, particularly after 1964. For example, average airborne concentrations in production areas of the plant decreased from 0.72 mg/m3 in the 1940s to 0.27 mg/m3 from 1950 to 1964, and the average was 0.039 mg/m3 after 1964. Former workers were interviewed to determine activity patterns in the plant by job title. This information was combined with Cr(VI) monitoring data to calculate cumulative occupational exposure for each worker. Cumulative exposures ranged from 0.003 to 23 (mg/m3) x years. The highest monthly 8-hour average exposure concentration for each worker ranged from 0.003 to 4.1 mg/m3. These exposure estimates have been combined with mortality data for this cohort to assess the lung cancer risk associated with inhaled Cr(VI), and a positive dose-response relationship was observed for increases in lung cancer mortality with measures of cumulative exposure and highest monthly exposure.

60 years of chemical carcinogens: Sir Ernest Kennaway in retirement.

1992 marks the sixtieth anniversary of the publication of the first paper on the production of cancer by pure hydrocarbons, by the team at the Chester Beatty Research Institute headed by Professor Kennaway. Studies on polycyclic aromatic hydrocarbons and other chemical carcinogens continued to thrive under his leadership in succeeding years at the Chester Beatty and beyond, into his 'retirement' in 1946. He played a key role in stimulating research on factors contributing to the epidemic of lung cancer that became apparent by then, and with the support of the Medical Research Council (MRC) and other organizations he directed a small team working on analytical and epidemiological studies in a makeshift laboratory at St Bartholomew's Hospital. Published work included the identification and determination of benzo(a)pyrene in domestic soot, urban air pollution, motor vehicle exhausts and cigarette smoke, also arsenic in urban air and cigarette smoke, radon in indoor air and carbon deposits in human lungs. Such studies have been pursued in other laboratories around the world since then, and many of the lines of enquiry are traceable back to the pioneering work of the team at the Chester Beatty 60 years ago.