Yamagiwa and Ichikawa

In the latter part of the nineteenth century, workers in the paraffin refining, shale oil, and coal tar industries had high incidences of skin cancer. A possible cause emerged during the period 1915-1918 when Japanese scientists discovered that painting the ears of rabbits and mice with coal tar extracts produced tumors, some of which were malignant (Yamagiwa and Ichikawa, 1918). 

The discovery that exposure to exogenous chemicals could lead to cancer in humans was first made in the late 18th century, when Percival Pott demonstrated the relationship between cancer of the scrotum and the occupation of chimney sweepers exposed to coal tar/soot. Other examples noted later were scrotal cancers in cotton spinners exposed to unrefined mineral oils, and cancers of the urinary bladder in men who worked in textile dye and rubber industries due to their exposure to certain aromatic amines used as antioxidants. Experimental induction of cancer by chemicals was first reported in detail by Yamagiwa and Ichikawa in 1918, when repeated application of coal tar to the ear of rabbits resulted in skin carcinomas. Over the next few years, Kennaway and Leitch confirmed this finding and demonstrated similar effects in mice and rabbits from the application of soot extracts, other types of tar (e.g., acetylene or isoprene), and some heated mineral oils. These researchers also observed skin irritation sometimes accompanied by ulcers at the site of application of the test material. Irritation was thought to be an important factor in skin tumor development. However, not all irritants (e.g., acridine) induced skin cancer in mice and conversely, some purified chemicals isolated from these crude materials... 

Benzo[a]pyrene. Benzo[a]pyrene is a potent experimental skin carcinogen, and it is often used as a positive control in bioassays of other agents. Mixtures of PAHs that include benzo[a]pyrene such as coal tar were shown to be dermal carcinogens in animals as early as 1918 (Yamagiwa and Ichikawa 1918). In its role as a positive control, benzo[a]pyrene is usually administered at a single dose level, and thus quantitative evaluation of dose-response relationships is not possible. 

Within twenty-five years of the first successful experiments to produce tumors in animals by skin painting with solutions of coal tar by Yamagiwa and Ichikawa (4361) and... 

Because of the successful induction of cancer in a laboratory animal by Yamagiwa and Ichikawa (4361) and the discovery that several PAHs were tumorigenic when painted on the skin of laboratory animals (194, 797, 2078), the tumorigenicity of literally hundreds of PAHs (and structurally similar nitrogen analogs) and their alkyl derivatives was studied from 1932 to 1941. Many of the assertions made about the correlation between the laboratory findings and human experience were extremely farfetched and caused much confusion. This led to the request for Shear of the U.S. National Cancer Institute to attempt to return order to the field of carcinogenicity. The result was the classical description by Shear and Leiter (3627), a description whose pertinence is still valid. 

Cancer of the skin became the first experimental model of chemically induced cancer in 1915 when Yamagiwa and Ichikawa/ in Japan, induced skin carcinomas in the ears of rabbits by repeated topical applications of coal tar for long periods (see ). In 1918, Tsutsui induced skin cancer in mice with tars and/ in 1922, Passey induced skin cancer in mice with ether extracts of tars (5). 

Yamagiwa, K., and Ichikawa, K. (1915). Experimentelle Studie fiber die Pathogenese der Epithelialgeschwfilste. Mitt Med Fac Kaiserl Unix Tokyo 15, 295-344. 

The Japanese, Katsusaburo Yamagiwa and Koichi Ichikawa, also carried out experiments at the beginning of this century, which indicated that coal tar fractions could cause cancer in mice. 

Yamagiwa, K. Collected papers on artificial production of cancer Maruzen Company Ltd., Tokyo, Japan (1965) Yamagiwa, K. and K. Ichikawa ExperimenteUe Smdie fiber die Pathogenese der Epitheliengeschwfilste [Experimental study of the pathogenesis of epithelial tumors] Tokyo Igakkai Zassi 15 (1915) 295-344 Experimental study of the pathogenesis of carcinomas J. Cancer Res. 3 (1918) 1-29. 

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