In this chapter, we discuss the diseases and related pathologic alterations that may be encountered in the gastrointestinal tract and associated organs of various species of laboratory animals, birds, fish, reptiles, and amphibians. Diseases of various segments of the gastrointestinal tract, the salivary glands, liver, and pancreas are discussed and categorized as inflammatory, parasitic, neoplastic, or miscellaneous. The latter category includes developmental anomalies and metabolic lesions. Due to space limitations, this presentation is not an all-inclusive review, but it does provide a rather extensive review of these lesions. We have also included a rather comprehensive literature review, with a list of references for those readers who want more detailed information with respect to specific diseases.

The Digestive System

Publisher Summary This chapter reviews the sequence of cellular and other changes during cancer development in selected sites in experimental animals and in humans. It highlights the similarities and differences among the carcinogenic processes and discusses the evident generalities and working hypotheses derived from the analyses. It also discusses some perspective concerning the possible relationship of carcinogenesis to other types of chronic pathological processes such as some forms of adaptation and evolution. Major emphasis is given to three sites—namely, skin, liver, and breast. Several other sites or types of neoplasms are also discussed in the chapter, including urinary bladder, brain, kidney, uterine cervix, and foreign-body sarcoma. It focuses on the development of cancer with chemicals in experimental animals and in humans. To date, the major evidence for a beneficial role for new cell populations occurring during the preneoplastic phase of carcinogenesis concerns the liver. However, it seems appropriate to explore other systems from this point of view. In other organs or tissues, appropriate physiological or environmental factors should be sought as possible influences on early carcinogen-induced new cell populations. These influences might well constitute naturally occurring “promoting” environments in at least some carcinogenic process.

The sequential analysis of cancer development.

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 (ES...

Proliferative and nonproliferative lesions of the rat and mouse hepatobiliary system.

The preceding paper described our numerical index of carcinogenic potency, the TD50 and the statistical procedures adopted for estimating it from experimental data. This paper presents the Carcinogenic Potency Database, which includes results of about 3000 long-term, chronic experiments of 770 test compounds. Part II is a discussion of the sources of our data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Part III is a guide to the plot of results presented in Part IV. A number of appendices are provided to facilitate use of the database. The plot includes information about chronic cancer tests in mammals, such as dose and other aspects of experimental protocol, histopathology and tumor incidence, TD50 and its statistical significance, dose response, author's opinion and literature reference. The plot readily permits comparisons of carcinogenic potency and many other aspects of cancer tests; it also provides quantitative information about negative tests. The range of carcinogenic potency is over 10 million-fold.

A carcinogenic potency database of the standardized results of animal bioassays

Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53.

Summary Aflatoxin B1 has been administered to newborn and infant C57BL × C3H F1 mice for a further evaluation of its hepatocarcinogenicity in this species. To date, adult animals have been shown to be relatively refractory. One-, 4-, or 7-day-old groups of animals were exposed to either single or limited numbers of i.p. injections of aflatoxin B1. Animals selected at random were sacrificed at 52 and 82 weeks of age. Newborn animals appeared to be more prone to the lethal effect of aflatoxin B1 than did the 4- or 7-day-old infants. Male infants developed hepatomas by 52 weeks of age. At 82 weeks, both tumor incidence and tumor mass increased in all male groups. Seven-day-old treated females developed hepatomas, although at a low incidence rate. Thus, it has been demonstrated that aflatoxin B1 is a potent hepatocarcinogen under the experimental conditions. It has been concluded that the infant age and the male hormonal environment were factors favorable for the inception and expression of liver neoplasia in mice.

https://cancerres.aacrjournals.org/content/canres/32/11/2289.full.pdf

Aflatoxin B1, a Hepatocarcinogen in the Infant Mouse

A series of studies pertaining to perinatal carcinogenesis have been reviewed. Their main objective was development and definition of a sensitivity biologic model for carcinogenicity screening. Data were summarized on factors modifying the carcinogenic response of various tissues following transplacental, neonatal-infant, or adult exposure of (B57BL/6J X C3HeB/FeJ)F1 mice to a single administration of ENU. In addition, tumor response of mice treated during specific perinatal age periods with DEN, BP, aflatoxin B1, benzidine . 2HCl, DDT, dieldrin, and safrole were analyzed. The results revealed that the age of the animals at the time of carcinogenic exposure has been the most effective modulator of carcinogenesis in liver, lung, stomach, ovary, and lymphoreticular tissues. Infancy proved to be the most susceptible period to carcinogenesis as demonstrated by a great variety of tissues that responded to treatment and the incidence of tumors which developed. Depending on the nature of carcinogen, variation in organ sites undergoing carcinogenesis was considerable, apparently due to difference in their enzymatic competence to activate and metabolize the agent. Thus a single treatment with ENU, a spontaneously activated type of procarcinogen, induced 59 primary types of tumors in 22 tissues. In contrast, treatment of infants by procarcinogens requiring enzymatic activation led to development of tumors only at a limited number of tissue sites. However, regardless of the type of carcinogen used, the liver consistently responded with development of tumors. Detailed morphologic and biologic evaluations of the induced liver tumors demonstrated in addition to the benign neoplastic variety, the presence of the frank malignant tumors. The character of tumors was dependent not only on carcinogenicity of the agent used but also on the age of mice at the time of carcinogenic treatment. Perinatally induced primary liver tumors showed greater tendency to metastasize and were more readily transplantable into an isogeneic host than those induced at later age periods. Data showed the advantage of prenatal and/or postnatal treatment in combination of life-long exposures to test agents as a more sensitive bioassay system in comparison with solely postweaning treatment. Because the early age period is the most sensitivity life phase to carcinogenesis, it appears to be a good model for prescreening various potential carcinogens, especially when only small amounts of test substances are available. The importance of the proper relationship of such bioassay to the other test systems regarding assessment of potential human risk has been emphasized.

Neoplastic response of mouse tissues during perinatal age periods and its significance in chemical carcinogenesis.

Summary The modifying role of age, sex, and strain upon the incidence, multiplicity, and spectrum of tumors induced by ethylnitrosourea, a short-acting carcinogen, has been studied. The first-generation (F 1 ) hybrids of C57BL/6J × C3HeB/FeJ and C3HeB/FeJ × A/J mice of both sexes were given single i.p. injections (60 or 120 µg/g) of ethylnitrosourea at 1, 15, or 42 days of age. Experimental animals were left to live their life-span, while the control groups were killed at 52, 90, 142, and 170 weeks of age, respectively. Animals treated with ethylnitrosourea died, in general, by the 90th week of age due to development of tumors mainly in lung, liver, Harderian glands, stomach, ovaries, lymphoreticular system, kidneys, mammary gland, uterus, and nervous system. In contrast, few of the controls died during that same observational period. The age of mice at the time of exposure to the carcinogen was one of the most important modifiers of tumor development in lung, liver, Harderian glands, stomach, kidneys, lymphoreticular system, nervous system, ovaries, and mammary glands. The sex of the animals influenced the development of liver tumors, Harderian gland tumors, and malignant lymphomas. The C3HeB/FeJ × A/J F 1 hybrids more readily developed lung tumors, while the C57BL/6 × C3HeB/FeJ F 1 mice were more susceptible to liver, Harderian gland, lymphoreticular system, ovarian, and mammary gland carcinogenesis.

https://cancerres.aacrjournals.org/content/canres/34/10/2530.full.pdf

Development of Broad Spectrum of Tumors by Ethylnitrosourea in Mice and the Modifying Role of Age, Sex, and Strain

The metastatic capabilities of well-defined nodular hepatic lesions induced by benzo( a )pyrene, ethylnitrosourea, benzidine · 2HCl, and diethyInitrosamine were evaluated. Coded liver and lung tissues from 1264 treated C57BL/6J × C3HeB/FeJ F1 mice were assessed independently for the presence of primary nodular lesions and metastases, respectively. Primary lesions were classified according to their size, cell morphology, and growth patterns into hyperplastic, adenomatous, and trabecular nodules. None of the 126 mice bearing hyperplastic nodules had pulmonary metastases. Four of 291 (1.4%) mice with adenomatous nodular lesions showed metastases. In contrast, of the 733 mice bearing the trabecular type of nodular lesions alone or in combination with other lesions 266 (36%) showed pulmonary metastases. The pulmonary metastases were first detected in mice dying between 51 and 60 weeks of age (5%). This rate increased as a function of age at death, reaching an incidence of 51% in mice surviving more than 81 weeks. It was concluded that nodules showing trabecular and the more anaplastic solid sheet type of growths represented bona fide hepatocellular carcinomas in the mouse.

https://cancerres.aacrjournals.org/content/canres/38/7/2003.full.pdf

Morphology and metastatic nature of induced hepatic nodular lesions in C57BL x C3H F1 mice.

The modifying effect of partial hepatectomy and gonadectomy upon carcinogenesis in general and hepatocarcinogenesis in particular has been evaluated in 6-week-old C57BL/6J × C3HeB/FeJ F1 mice. Ethylnitrosourea (60 µg/g body weight) was administered once after sham hepatectomy or 48 hr following partial hepatectomy at which time DNA synthesis in the regenerating liver was 30-fold higher than in the sham-hepatectomized mice. Six days later, one-half of the partially hepatectomized and one-half of the sham-operated mice were gonadectomized. Survivors were killed at 90 weeks of age. The incidence of tumors has been evaluated at all tissue sites. The sex hormonal environment of the hosts was assessed by histological evaluation of kidneys and adrenal glands. This evaluation showed that following gonadectomy, the morphology of the above tissues and consequently the hormonal environment shifted from that observed in the intact mice towards one characteristic of the opposite sex, assuming an intermediate state. Although primary tumors developed at several sites, partial hepatectomy and gonadectomy modified primarily the development of liver tumors. Thus, partial hepatectomy enhanced significantly hepatocarcinogenesis in male but not in female mice, resulting in an increased difference in the incidence of liver tumors between the two sexes. Gonadectomy of males abolished the enhancing effect of partial hepatectomy upon ethylnitrosourea hepatocarcinogenesis while ovariectomy potentiated development of liver tumors, leading to a similar incidence of liver tumors in both castrates. Modulating effects of hepatectomy and gonadectomy operated by influencing the incidence of benign rather than malignant liver tumors. The ovariectomy of partially hepatectomized females also enhanced kidney tumorigenesis. Data suggested that since enhancing effect of partial hepatectomy was associated with increased macromolecular (DNA) synthesis at the time of the administration of carcinogen initiation and the change of hormonal environment coincided with promoting phase of hepatocarcinogenesis, the respective conditions operated independently by two different mechanisms.

/pdf/modifying-role-of-partial-hepatectomy-and-gonadectomy-in-52hina6v5b.pdf

K. V. N. Rao

Papers

Aflatoxin B1, a Hepatocarcinogen in the Infant Mouse

Neoplastic response of mouse tissues during perinatal age periods and its significance in chemical carcinogenesis.

Development of Broad Spectrum of Tumors by Ethylnitrosourea in Mice and the Modifying Role of Age, Sex, and Strain

Morphology and metastatic nature of induced hepatic nodular lesions in C57BL x C3H F1 mice.

Modifying role of partial hepatectomy and gonadectomy in ethylnitrosourea-induced hepatocarcinogenesis.