In Memoriam: Honorary Member Nobuyuki Ito, MD, PhD, 1928-2010
Recently the scientific world, particularly
toxicologic pathology, lost one of its great leaders,Nobuyuki Ito, MD, PhD, who passed away on October
6, 2010 in Nagoya, after nearly 5 years battling illness.
He was 81.

In his academic life, Dr. Ito left behind alegacy of leadership and advancement of toxicologic
pathology, toxicology, and research on chemical
carcinogenesis. He received the 2005 Education Award
from the Society of Toxicology celebrating recognitionof his lifelong contributions to scientific andprofessional education. Dr. Ito began his pioneering
efforts in toxicology education 35 years ago when heestablished an extensive teaching and training program
for toxicologists at the Department of Pathology,
Nagoya City University Medical School. He trained
two generations of toxicologists and toxicologic
pathologists in Japan and several from other countries,
first as Chairman of the Department, then as Dean of
the Medical School and lastly as President of theUniversity. Dr. Ito and his students and seniorscientists have made significant contributions to risk
assessment and regulation of chemicals and foodadditives in Japan and internationally. His works in thefield of histogenesis and modulation of the neoplastic
process and on antioxidants in anti-carcinogenesis
have been acknowledged by many societies, including
the Princess Takamatsu Cancer Research Fund, theJapanese Cancer Association, and the International
Federation of Societies of Toxicologic Pathology.
During his distinguished career at Nagoya City

University Medical School. Dr. Ito authored andco-authored with his numerous students and associates
more than 600 peer-reviewed scientific publications.
His former students, numbering more than 100, are inprestigious and important positions around the world,continuing his task of educating toxicologists in Japan,Korea, Thailand, Brazil and the United States.
Born in Kyoto, Dr. Ito graduated fromNara Medical University, Nara, 1952, received hisD.Ms. (Ph.D.), 1961, from Osaka University School ofMedicine, and began his academic faculty career in1954. He studied hepatocarcinogenesis from 1962 to1964 in the laboratory of Professor Emmanuel Farber,
University of Pittsburgh. He was very impressed by
how well equipped the research facility was and theoverwhelming amount of material available at theUniversity of Pittsburgh. His experience in Farber’slaboratory very much influenced his fundamental
research attitude, direction and system after his returnto Japan.
In 1972, he became chairman andprofessor at the Department of Oncological Pathology,
Cancer Center, Nara Medical University, based on his
extensive and productive research activities. In 1974,
he became chairman and professor of the First
Department of Pathology, Nagoya City University
Medical School, Nagoya, following Professor
Hisamasa Sato who had been his teacher at Nara
Medical University. Dr. Ito’s research base wasanchored to Nagoya thereafter as professor, as Dean
and then president of the University and continuing as
Emeritus Professor until his unfortunate terminal
illness.
His career as a researcher of in vivo
chemical carcinogenesis and as a pathologist began
upon his graduation from Nara Medical University andhis significant contributions to carcinogenesis,
toxicology, toxicologic pathology and risk assessment
cannot be expressed simply by word. He has provided
the fundamental research needed for the assessment ofnumerous synthetic and natural chemicals that areintroduced into the environment. He was the first to
demonstrate carcinogenic activity of many chemicals,
including α-benzenehexachloride (α-BHC; a pesticide),quinoline(industrial
chemical),butylatedhydroxyanisole (BHA; food additive used as anantioxidant), catechol (a natural antioxidant),
2-amino-1-methyl-6-phenylimiazo [4,5-b] pyridine(PhIP; meat pyrolysate product) and captafol (apesticide). Best known for his research on one foodadditive, BHA, this revolutionized the field ofcarcinogenesis research and led to a consensus within
the scientific community that regulatory actions should
be decided after thorough examination of both thebenefit and risk of the chemicals and utilizing all of theresearch available about them, not just relying on theoutcome of long term rodent bioassays. After his
publication of the carcinogenicity of BHA, previously
considered as safe and possibly a chemopreventive

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agent, heated discussions by many experts from U.S.A,
England, Europe, Canada and Japan took place. It wasdecided not to ban BHA since it is carcinogenic only atvery high doses, the carcinogenic target organ inrodents is the forestomach which humans do not have,
it is not genotoxic, and it is a very useful food additive
antioxidant. His1983 report on BHA changed theconsensus approach regarding risk assessment ofcarcinogenic substances, particularly non-genotoxiccarcinogens. After his pioneering work with BHA, thephrase “before Ito and after Ito” was often used among
researchers recognizing this landmark decision. Afterdiscovery of BHA carcinogenicity in rats, Ito’s group
discovered other natural carcinogenic antioxidants
present in plants, including catechol, sesamol, caffeic
acid, hydroquinone and 4-methoxyphenol. The
research on antioxidants was further extended tostudies on modification of chemical carcinogenesis byantioxidants and led to the conclusion that themodification by antioxidants depends upon the targetorgan; an inhibitory effect could occur in one organ but
enhancement in other organs.
Dr. Ito also concentrated on developing
and improving animal models for the study of cancersof the prostate, urinary bladder, kidney, stomach,intestine and liver. He developed a new in vivo systemusing male rats which is capable of detecting thecarcinogenicity of chemicals in a relatively short time
(8 weeks) with high sensitivity and specificity. Thissystem, known as the medium-term liver bioassay
system, was approved as an alternative carcinogenicity
screening method by the International Conference on
Harmonization of Technical Requirements forRegulation of Pharmaceuticals for Human Use (ICH).
The system consists of an initial i.p. injection ofdiethylnitrosamine (DEN) as initiator followed by theadministration of the test compound for 6 weeks
beginning 2 weeks after the initiation with 2/3 partial
hepatectomy on week 3. The development ofpreneoplastic lesions in the liver is quantitatively
analyzed as glutathione S-transferase placental(GST-P) form-positive foci by immunohistochemical
visualization. Dr. Ito’s group has evaluated 313
chemicals over the past 20 years, with more than 100
publications reporting the data that demonstrate its
feasibility and reliability. In addition, he alsoestablished a multi-organ carcinogenicity screening
system using rats.
Dr. Ito was a superb scientist and mentor,
constantly seeking new ideas, and directing, training
and mentoring numerous young researchers
worldwide.
He had boundless energy and enthusiasm,
and provided significant leadership for many scientificsocities in Japan and internationally. In Japan, theseincluded the Japanese Society of Toxicologic
Pathology (JSTP), the Japanese Society ofPathology(JSP) and the Japanese Cancer Association(JCA). He served as President of JSTP for 5 years,
developing it as a significant professional society. He
took charge of office functions and established themanagement and infrastructure of the society. He
served as president of the annual scientific meeting ofJSTP in 1987. He was also instrumental in founding
the International Federation of Societies of Toxicologic
Pathology (IFSTP), and organized its first international
conference while he was president in 1992, held inNagoya. This was but one of the many local, nationaland international meetings he organized, always
memorable for their scientific and social content. Hewas President of the 52nd Annual Meeting of JCA thatwas successfully held in Nagoya in 1994. The JapaneseSociety of Food Chemistry was also one of his major
areas of effort, serving as president from 1999 to 2002.
He also contributed in significant ways to the Societyof Toxicologic Pathology (STP), Society of Toxicology(SOT) and the American Association of Cancer
Research in the U.S.A.
Recognized internationally for his
scientific contributions, Dr. Ito was named tonumerous panels, advisory boards and committees inJapan, in the U.S.A. (Food and Drug Administrationand Environmental Protection Agency), and theInternational Agency for Research on Cancer andWHO/FAO Joint Meeting on Pesticide Residues. Hewas also chairman of the Food Safety Committee ofthe Ministry of Health and Welfare, Japan.
Dr. Ito’s expertise, contributions, andsustained excellence were recognized with numerous
other awards and honors. He received the Award of thePrincess Takamatsu Cancer Research Fund (1985,Tokyo), the Chu-nichi Cultural Award (1985, Nagoya),
theRobertE.
Greenfield
Lectureship
inCarcinogenesis (1989, Omaha, U.S.A), Yomiuri Tokai
Medical Award (1991, Nagoya), Honorary Doctor ofscience Degree from University of Nebraska MedicalCenter (1994, U.S.A.), Medal with Purple Ribbon(1995), the Takeda Prize for Medical Science (1995,Osaka), Honorary Doctor of Science Degree fromUniversity of Cagliari (1996, Italy), Tomizo YoshidaAward of JCA (1996, Tokyo), the Kitashi-Mochizuki
Memorial Award (2002, Shizuoka), and the Order of
the Sacred Treasure, Gold and Silver Star (2003).
Throughout his long and distinguishedcareer, Dr. Ito has touched and developed a tremendous
number of scientists in toxicologic pathology, as wellas in toxicology, pathology, and carcinogenesis. Theyand his family made Ito’s world, and he will be forever
remembered with gratitude, admiration, respect, andfriendship.

Tomoyuki Shirai MD., PhD.
Nagoya City University Graduate School of Medicines, Department of Experimental
Pathology and Tumor Biology

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