Gerald M. Lower

Concepts in causality: Chemically induced human urinary bladder cancer

A significant portion of the incidence of human urinary bladder cancer can be attributed to occupational and cultural (tobacco smoking) situations associated with exposures to various arylamines, many of which represent established human carcinogens. A brief historical overview of research in bladder cancer causality indicates that the identification of causal agents and causal mechanism has been approached and rests upon information gathered at the organismal (geographical/historical), cellular, and molecular levels of biologic organization. This viewpoint speaks of a natural evolution within the biomedical sciences; a natural evolution from descriptive approaches to mechanistic approaches; and a natural evolution from more or less independent discipline‐oriented approaches to hierarchically organized multidisciplinary approaches.

Enzymic deacetylation of carcinogenic arylacetamides by tissue microsomes of the dog and other species

The relative ability of arylacetamide deacetylase enzyme systems of dog liver to carry out the deacetylation of the carcinogens, 4-acetylaminobiphenyl, 2-acetylaminofluorene, and 2-acetylaminaphthalene, was examined. The arylacetamides were incubated with unfortified dog liver microsomes, and enzyme activity (nmol arylamine/mg protein/hr) was estimated by colorimetric quantitation of the resulting arylamines. The dog liver enzyme system displayed characteristics similar to those described for the rodent liver enzyme system in that enzyme activity was greatest in liver tissue, was localized in the microsomal subcellular fraction, required no cofactors, and was inhibited by heat, sodium fluoride, and thiol reagents. In five replicate assays, the relative rates of deacetylation were about 10, 6, and 1 with 4-acetylaminobiphenyl (84.8 +/- 12.4), 2-acetylaminofluorene (52.5 +/- 5.1), and 2-acetylaminonaphthalene (8.8 +/- 3.3), respectively. As a canine urinary bladder carcinogen, 4-acetylaminobiphenyl is considered more potent than 2-acetylaminofluroene, while 2-acetylaminonaphthalene is devoid of detectable carcinogenic activity, despite the fact that 2-aminoaphthalene is a well-established canine urinary bladder carcinogen. Removal of the acetyl group may be a requirement for urinary bladder carcinogenesis; accordingly, the present studies demonstrate the appearance of a direct relationship between dog liver deacetylase enzyme specificity and urinary bladder susceptibility to these carcinogenic arylacetamides.

Arylamines and bladder cancer causality: Application of conceptual and operational criteria

Clinical Pharmacology and Therapeutics (1983) 34, 129–135; doi:10.1038/clpt.1983.141

Risk, susceptibility and the epidemiology of proliferative neoplastic disease: Descriptive vs. mechanistic approaches

Recently there has been a confusing and somewhat frustrating difference of opinion in epidemiology concerning the relative merit and utility of descriptive versus mechanistic knowledge in approaching the comprehension and control of human cancer. This distinction has both historical and evolutionary rationale; it generally being necessary to know something of WHAT is happening before one can be legitimately concerned with HOW it is happening. As outlined below, however, there is little justification for making value judgements based on this distinction, and the situation is more one in which descriptive approaches and mechanistic approaches are equally essential in the development of a systematic viewpoint, a viewpoint providing guidance to meaningful intervention.

Systematic epidemiologic theory: Conceptual foundations and axiomatic elements

Since the initial epidemiologic confrontations of chronic, non-infectious diseases during the 1940s, there has emerged a periodic concern among epidemiologists regarding disciplinary boundaries and identity. With the development of hierarchical views of the natural history of human disease, the elaboration of mutation theories of chronic, non-infectious disease, and the identification of conceptual frameworks and causal relationships applicable to both the infectious and chronic, non-infectious diseases, it has become possible to reconsider the definitions and scope of epidemiology from within the confines of general epidemiologic-pathologic theory. Based upon natural history and discipline-related concepts of causation, it is possible to integrate the epidemiological and pathological characteristics of disease into a single, coherent systematic epidemiologic theory. Within these conceptual/axiomatic frameworks, systematic epidemiology emerges as the study of disease causality and control and is generally applicable to both the infectious and the chronic, non-infectious (i.e., neoplastic) diseases. Because epidemiologic theory begins with pathologic theory, it is fitting that systematic epidemiologic theory embrace both epidemiology and pathology as complimentary conceptual approaches to the comprehension of disease. Because the interdependent efforts of epidemiology and pathology provide the conceptual basis for action, it is also fitting that systematic epidemiologic theory embrace preventive medicine and public health as operational approaches to the control of disease.

DIVERSE ORIGINS OF UBIQUITOUS ENVIRONMENTAL CARCINOGENIC HAZARDS AND THE IMPORTANCE OF SAFETY TESTING1

A vast array of chemical carcinogens are present in the environment, many of natural origins and many as a result of mans use and abuse of technology. The background occurrence of such chemical ha...

Thin-layer chromatography: a non-specific method for demonstrating carcinogen-DNA interactions.

Abstract The utilization of thin-layer chromatography revealed an apparent interaction of native calf thymus DNA with two carcinogens: 4-nitroquinoline-N-oxide and the 8-methyl ether of xanthurenic acid. Similar results with 2,6-quinolinediol, l -kynurenine and anthranilic acid were observed. The observed “binding” of these compounds to DNA at the origin of the chromatograms was related to physical occlusion of the solvent by the DNA and retardation of normal solvent flow through the DNA spot. The test compounds were physically trapped within the DNA spot and could not be eluted by the solvent to give their normal R F values. Thhese inherent problems with thin-layer chromatography have precluded its use as positive proof of interaction of water-soluble carcinogens with DNA.

Van Rensselaer Potter: A Memoriam

I first met Van Potter nearly 40 years ago when I was 17 and entering the University of Wisconsin as a new freshman. During the summer of 1963, Van was a participant in a series of evening seminars designed to familiarize premed students to the community at the University of Wisconsin Medical School. I was immediately struck by Vans unique ability to cut straight to the core of virtually any issue having to do with biomedicine. As with many of his students, I quickly found myself in a father-son relationship of both our making. Van has been a source of inspiration and guidance to me ever since.

GUIDELINES FOR PRODUCTION OF FOOD ADDITIVES AND OTHER CHEMICAL COMMODITIES WITH LEAST CARCINOGENIC POTENTIAL: A BIOCHEMICAL APPROACH1

An attempt has been made, using a biochemical approach, to construct safety guidelines for synthesis and production of food additives and other chemical commodities with “least carcinogenic potential.” In general, chemical carcinogens exist as or are metabolically activated to reactive forms able to interact with biologically-important macromolecules, a process apparently directly related to carcinogenesis by chemicals. A working knowledge of the biochemistry of biologically-foreign compounds is therefore necessary to understand structure-activity relationships observed in chemical carcinogenesis, since it appears that carcinogenic activity can be a consequence of the structure of the chemically-reactive forms of a carcinogen rather than of the structure of the parent compound. Consequently, the biochemistry of foreign compounds, the metabolic activation of various chemical carcinogens, and the nature of the probable active forms of these carcinogens has been briefly reviewed. Utilization of this knowledg...