Document 6052v05jmMaJ0VEqGYNp60b9

1 of the glands predisposed lo the devel opment of Urge mucous cysts. Glands of the fundic area which normally con tain a variety of secretory ceil types consisted primarily of mucus-secreting cells. Widespread penetration of the muscularis mucosae and invasion of the submucosa by the mucosal epithelium (Fig. 1) was observed in the stomach of each experimental animal. Large cystic areas filled with mucus and lined with elongated mucus-secreting epithelial cells predominated in the subniucosa. Other cells assumed a glandu lar pattern. Serial sections of the sub mucosal cysts demonstrated stratified arrangements of proliferating epithelial cells which penetrated the basal lamina and invaded the surrounding connective (issue of the submucosa (Fig. 2). Epithe lial origin of the stratified cells was determined by the presence of nucleoli and similarity of the nuclei in size and shape to the nuclei of the epithelial cells lining the cysts. Occasionally, ir regular hyperchromic nuclei and pleo morphic ceils with mitotic figures were present in the cells of the stratified areas. The presence of inflammatory cells in the submucosa in proximity lo the glandular and cystic changes was common. The increased cellularity of the mucous glands with invasion of the muscularit mucosae and accompanying inflammation noted above is histologi cally described as a hypertrophic gastritis. The extension of the mucosal epithelial cells into the submucosa and :he presence of irregular stratified arraogemeats of epithelial ceils within the tubmucosa are distinctly dysplastic pat ents. The experimental concentration >f biphenyls (300 ppm) within ihe diet vhich was sufficient to produce these ondiiiom in subhuman primates in 3 nonihs is about ten times the levels hat have occurred in samples of milk 28 ppm) and of fish (35 ppm) re* 'Qrtcd by the U.S. Food and Drug administration (2). This concentration ; much less than the level* that have ccurrcd in food products due to inustriai accidents (2000 to 3000 ppm) *). The magnitude of the chronic cf:ds whtch could be produced by PCfliduccd hypertrophic gastritis is us yet ndctcTmincd. The nausea and vomiting allowing human consumption of PCB's it possibly a result cf the gastric irritaiins. Weight loss by the experimental Fig. 2. Glandular epithelial cells that havp extended from the maeoen Imo d* mucosa encompass Urge cysts (C). In some areas (-*) the epithelial esfla an stratified and penetrate into the connective iHtue of the submocoea. The cell --H of the stratified area is similar in site and appearance to that of tha simple *--f epithelium that tines the remainder of the cyst (sea Inset). Serial sections of the tissue confirmed the stratified arrangement of the epithelial cells (X250, Ihm| xttfi; trait represents 50 pin). monkeys and human patients exposed to the PCB's may be related to gastri tis, Replacement of ihe parietal eells by the mucus-secreting cells which oc curred in the fundic glands of the more severely affected animals may re sult in achlorhydria and eventual pernicious anemia owing to the lack of intrinsic factor necessary for vitamin D)3 absorption. Invasion of the muscularis mucosae and submucosa by the epithelial elements may lead to toss of integrity of the gastric wall with even tual erosion, ulceration, and hemor rhage, as was the case in monkeys fed chlorinated biphenyl dioxins {12), Decause interest in these environ mental contaminants is only recent, in vestigative efforts have not yet deter mined the long-term carcinogenic poten tial of PCB's and PCTs. The associa tion of chronic irritation with cancer, particularly of the stomach, cervix, oral mucosa, and bronchial epithelium, is well documented. These dyspla&tic cel lular abnormalities of the hypertrophic gastric mucosa are likely due to chronic irritation but arc at present short of neoplastic transformation. The develop ment of hypertrophy, hyperplasia, and dysplasia of the gastric mucosa of sub human primates necessitates clarifies- lion of the carcinogenic potentials of these compounds. J. It Allsn D. H. Nmmck Department of Pathology, Medical School, and Regional primate Research, Center, University of Wisconsin, Madison 53706 t. a. w. atwbteu*. r. whim, a m. r***A 3. O. Iltmu, M. N. Klr*M, Hmm XSS, I09S (IMS). 3. A. C. KrOtyn, Mmkm. SMS ftfpx. f, IS (l72). 3. O. p. Frits, UK, p. 3S. 4. A. R. Yob*, OM, p, 7V. 5. M. XuntsiiM, T. Ywfclwwra. J. Munnkfl, A. Ymw(wN, ibUt., p. Iff. C. 1. O. Vm, iM, p. MS. T. D. H. No*** me J. *. Alt*. FM. FMr. 1*. t (1970). S. M. NttUnmri. Art*. CmOm. W--kh II, S3S (1970). 9. J. L. Linear add D. a. PeakoO, Nmmn US, 71) (1970). 10. M. Otaws, F**M0ko.ttk*-ZmuAI, SS, 74 (1971). 11. 3. Sltmm me H. C. Cmn, /. Jsrte. M Chtm. J*, DOT (1970). 12. 7. R. Allen and U A. CtnNM, Anar. I, Vrt. art. )S. ISIS (IM7). 13. ThU work wi tuppertrd b HIH imm E50M72 and RR00IS7. and Whomtil Sea Gram Frocram. 20 October 1972 FKSnUAKY 1?7] HOMS 0 7 1 9 4 5 Polychlorinated Biphenyl- and Triphenyl-Induced Gastric Mucosal Hyperplasia in Primates Abstract. }*oh chinriiuited biphenyl or triphenyl ingestion by subhuman primates }ur 3 months produced hyperplasia and dysplasia of the gastric mucosa. The eon* centration 0/ the biphenyl within the experimental diet was less than an oedtr of magnitude greater than t! occurring in random food samples sold in the United States and less than levels which have occurred in food products as a result o) industrial accidents. The increased celhtlurify, abnormal dysplastic growth pattern, and tmasion of the adjacent tissue region indicate compromised gastric function and ore suggestive of an eventual neoplastic transformation. Polychlorinated biphenyls (PCB's) have been widely used in industry for over 40 years as sealants, heat transfer agents, plasticizers, adhesives, and dielec- trie fluids in capacitors and transform ers, Global environmental contamina tion (!) and their presence within the food chain have occurred through in dustrial accidents and improper dis posal and misuses of the compounds (2. J). Polychlorinated biphenyls were reported in the United Slates in coho salmon in 1969 and then in milk fat (28 parts per million), poultry and eggs (4.2 ppm), fish <35 ppm), and cereals (less than I ppm) (2). The Food and Drug Administration is presently re moving from the market known con taminated food samples which exceed 5 ppm. However, as a result of occult environmental and food exposure, significant levels of PCB's (over 1 ppm in adipose tissue) are present in over 30 percent of random samples taken from the general population of this country (4). Two separate, well-documenled in dustrial accidents resulted in high con- cemrations of PCB's in nee oil (2000 to 3000 ppm), wh.ch was subsequently consumed by over 1000 people (5), and in fish meal (14 to 30 ppm) used for poultry feed (2). The effects of PCB's on humans include acneform skin eruptions, pigmentation of nails and skin, eye discharge, generalized swelling, weakness, vomiting, diarrhea, weight loss, and fetal toxicity (5). Addi tional effects observed in experimental animals fed the compounds include hepatic porph>ria in chickens and rab bits (d), proliferation of hepatic smooth endoplasmic reticulum in rats (7), mice, and monkey > (o'), increase in certain hepatic enzyme activities in rats (7) and kes;ro!> iV), ncuopaihy in lais (10) . lymphopenia and immunosuppres sion in rabbits and guinea piets (6). and estrogenic activity in the rat uicrus (11) . In the study reported here dcr- natv'lopiu alo pecia, edema, and acneform lesions and hepatic alterations including organ hypertrophy and proliferation of the endoplasmic reticulum were observed in the subhuman primate. In addition, a previously unrcporied lesion, hypr plasia and dysplasia of the gasti mucosa, occurred in all animals th were fed diets containing the chiori ated biphenyls and triphenyls (PCT Male rhesus monkeys ranging in a from l lA to 2 years and having . average weight of 2.9 kg were used this study. Six animals were fed a di containing 300 parts of PCB (Aroel 1248) per million and six were giv 5000 parts of PCT (Arcelor 5460) p million in (he diet, for 3 months. Tl remaining three animals served as co trols. During the course of the expe. ment the animals were given access 400 g of (he experimental diet daii The animals continued to eat throug out the experimental period, althouthere was a decrease in body weight approximately 15 percent tit both of t! experimental groups. Within I mom all of the PCB-fed animals, and with 6 weeks, the PCT-fed animals, had h: loss from the head. neck, end back, progressive, generalized, subcutaoeo edema, particularly of the face, w manifested as swollen eyelids end 1i| A purulent discharge exuded from t eyes, and isolated acneform fesio were present on skin areas devoid hair. liver hypertrophy (2.3 percent the body weight in controls: 4.5 pc cent in the PCB group: 5.6 percent Jthe PCT group) was attributed main "to a proliferation of the smooth end plasmie reticulum observed elect* microscopically. Edematous thickeni of the stomach wall and marked hy p trophy of the pyloric and fundic fast, mucosa occurred. The hypertrophic gastric mucosa w several times thicker than the centt mucosa and was composed of grea* elongated hyperplastic glands coma, ing mucus-secreting cells (Fig. I). 1 cells containing basilar position, nuclei, abundant slightly teidopfu cytoplasm, large vacuoles, and a rr.cr villous border abutted on a basal lamir Prevention of discharge of the sect lion owing to the depth and appositi. Fig. I. <A) Normal pyloric glands of i gastric mucosa (Af) are separated f:c the submucosa (5) bv the mu^ala mucosne (m). (B) Following jtelycVa naled biphenyl ingestion the hyperp-u mucosni glands penetrate the mtisccla mucosae to form mucuvfilkd cyi? ef t suhrmicosx Cell* lini'ig c)>t similar area indicated by arrow (-) are msp fled in Fig. 2. (x4H: settle represent am). HONS 0 7 1 9 4 6