The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and differential diagnosis for classifying microscopic lesions observed in the hepatobiliary system of laboratory rats and mice, with color microphotographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available for society members electronically on the internet (http://goreni.org). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for lesions of the hepatobiliary system in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

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The Cesare Maltoni Cancer Research Center of the European Ramazzini Foundation has conducted a long-term bioassay on aspartame (APM), a widely used artificial sweetener. APM was administered with feed to 8-week-old Sprague-Dawley rats (100–150/sex/group), at concentrations of 100,000, 50,000, 10,000, 2,000, 400, 80, or 0 ppm. The treatment lasted until natural death, at which time all deceased animals underwent complete necropsy. Histopathologic evaluation of all pathologic lesions and of all organs and tissues collected was routinely performed on each animal of all experimental groups. The results of the study show for the first time that APM, in our experimental conditions, causes a) an increased incidence of malignant-tumor–bearing animals with a positive significant trend in males (p ≤ 0.05) and in females (p ≤ 0.01), in particular those females treated at 50,000 ppm (p ≤ 0.01); b) an increase in lymphomas and leukemias with a positive significant trend in both males (p ≤ 0.05) and females (p ≤ 0.01), in particular in females treated at doses of 100,000 (p ≤ 0.01), 50,000 (p ≤ 0.01), 10,000 (p ≤ 0.05), 2,000 (p ≤ 0.05), or 400 ppm (p ≤ 0.01); c) a statistically significant increased incidence, with a positive significant trend (p ≤ 0.01), of transitional cell carcinomas of the renal pelvis and ureter and their precursors (dysplasias) in females treated at 100,000 (p ≤ 0.01), 50,000 (p ≤ 0.01), 10,000 (p ≤ 0.01), 2,000 (p ≤ 0.05), or 400 ppm (p ≤ 0.05); and d) an increased incidence of malignant schwannomas of peripheral nerves with a positive trend (p ≤ 0.05) in males. The results of this mega-experiment indicate that APM is a multipotential carcinogenic agent, even at a daily dose of 20 mg/kg body weight, much less than the current acceptable daily intake. On the basis of these results, a reevaluation of the present guidelines on the use and consumption of APM is urgent and cannot be delayed.

BackgroundIn a previous study conducted at the Cesare Maltoni Cancer Research Center of the European Ramazzini Foundation (CMCRC/ERF), we demonstrated for the first time that aspartame (APM) is a multipotent carcinogenic agent when various doses are administered with feed to Sprague-Dawley rats from 8 weeks of age throughout the life span.ObjectiveThe aim of this second study is to better quantify the carcinogenic risk of APM, beginning treatment during fetal life.MethodsWe studied groups of 70–95 male and female Sprague-Dawley rats administered APM (2,000, 400, or 0 ppm) with feed from the 12th day of fetal life until natural death.ResultsOur results show a) a significant dose-related increase of malignant tumor–bearing animals in males (p < 0.01), particularly in the group treated with 2,000 ppm APM (p < 0.01); b) a significant increase in incidence of lymphomas/leukemias in males treated with 2,000 ppm (p < 0.05) and a significant dose-related increase in incidence of lymphomas/leukemias in females (p < 0.01), particularly in the 2,000-ppm group (p < 0.01); and c) a significant dose-related increase in incidence of mammary cancer in females (p < 0.05), particularly in the 2,000-ppm group (p < 0.05).ConclusionsThe results of this carcinogenicity bioassay confirm and reinforce the first experimental demonstration of APM’s multipotential carcinogenicity at a dose level close to the acceptable daily intake for humans. Furthermore, the study demonstrates that when life-span exposure to APM begins during fetal life, its carcinogenic effects are increased.

In the framework of a series of experiments conducted to evaluate the carcinogenic effects of oxygenated gasoline additives, MTBE was analyzed in an oral lifetime carcinogenicity study using 8-week-old male and female Sprague-Dawley rats. These experiments were part of a large research project on gasoline carcinogenicity performed at the Bentivoglio (BT) Castle Cancer Research Center of the Ramazzini Foundation and of the Bologna Institute of Oncology, MTBE, dissolved in oil, was administered by stomach tube at the doses of 1000, 250, or 0 mg/kg b.w., once daily, four days weekly, for 104 weeks. The animals were maintained until natural death. The last animal died 166 weeks after the start of the experiment, i.e., at 174 weeks of age. Under the tested experimental conditions, MTBE was shown to cause an increase in Leydig interstitial cell tumors of the testes and a dose-related increase in lymphomas and leukemias in female rats.