Document VJjB9wdv0d4ELp7yaagE3dXXN

JAM 3 0 1373 Polvclilorinatcd Iliphcnjl- and Triphcnyl-Induced Gastric Mucosal Hyperplasia in Primates Abstract. Potychlorinosrd biphenyl or triphenyl ingestion by s.'bhuman primates for $ months produced hyperplasia and dysplasia of the gastric n.ucosa. The con centration of the biphenyl within the experimental diet was hss than an order of magnitude greater than that occurring in random food samples sold in the United States and less than levels which have occurred in food products as a result of industrial accidents. The increased cellufartty, abnormal r'ytplastic growth pattern, and invasion of the adjacent tissue region indicate compromised gastric function and are suggestive of an eventual neoplastic transfornu tion. Polychlorinated biphenyls (PCB's) have been widely used in industry for over 40 years as sealants, heat transfer agents, plasticizers. adhesives, and dielec tric 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 {?, .1). Polychlorinated biphenyls were reported in the United States in coho salmon in 1909 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 front the market known eonlaminated food samples which exceed 5 ppm. However, as a result of occult environmental and food exposure, significant levels of PCB's (over I ppm in adipose ti>sue) arc present in over 30 percent of random samples taken from the general population of this country (<). Two separate, well-documented in dustrial accidents resulted in high con centrations of PCB's its rice oil (2000 to 3000 ppm), which 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 acncform skin eruptions, pigmentation of nails and skin, . eye discharge, generalized swelling, weakness, vomiting, diarrhea, weight loss, and fetal toxicity (5). Addi tional effects oVriwd in experimental animals led the compounds include hepatic porphyria in chickens and rab bit* (6). proliferation of hepatic smooth endoplasmic reticulum in rais (7), mice, and monkeys (5), increase in certain hepatic enzyme activities in rats (7) and kestrel* (9). neuropathy in rat* (10). lymphopenia and immunosuppres sion in rabbity and guinea pig* (rt). and estrogenic activity in the tat uterus (//). In the study reported here der matologic ahei.wions including alo- 4*1 pccia, edema, and ccncform lesions and hepatic alterations including organ hypertrophy and proliferation of the endoplasmic reticulum were observed in the subhuman primate. In addition, a HONS 08^399 previously unreported lesion, hypo plasia and dysplasia of the gastric mucosa, occurred in all animals that were fed diets containing the chlorin ated biphenyls and triphenyls (PCT**). Male rhesus monkeys ranging in ags from PA to 2 years and having an average weight of 2.9 kg were u>ed in this study. Six animals '-eie fed a diet containing 300 parts of PC B {Aroclor 1248) per million at.l i* were given 5000 parts of PCT (Aroclor 5460) per million in the diet, for 3 month*. The remaining three animals served as con trols. During the course of the experi ment the animals were given access to 400 g of the experimental diet daily. The animals continued to cat through, out the experimental period, although there was a decrease in body weight of approximately 15 percent m both of the experimental groups. Within I month, all of the PCB-fed animals, and within 6 weeks, the PCT-fcd animals, had hair loss from the head. neck, and back. A progressive, generalized, subcutaneous edema, particularly of the face, was manifested as swollen cycl'd, .i-J lips. A purulent discharge exuded from ihc eyes, and isolated acncform loicnt were (present on skin areas devoid of hair. J.iver hypertrophy *2.1 peteem of the body weight in controls: 4.5 per cent in the PCB group; 5.6 percent in the PCT group) was attributed mainly to a proliferation ol the smooth endo plasmic reticulum observed electron microscopically. Fdensatous thickening of the stomach wall and marked hyper trophy of the pyloric and fimdic gastric mucosa occurred. The hypertrophic gastric mm-os a wav several limes thicker tlun the control mucosa and was composed of greatly elongated hyperplastic gland; contain ing mucus-secreting cells (Tig. 1). The cells containing basilar positioned nuclei, abundant slightly acidophilic cytoplasm, large vacuoles, and a micro villous border abutted on a Vasal Umini*. Prevention of discharge of the secre tion owing to Ihc depth and apposition Pig. I. (A) Normal pyloric gland* of th; fiavtiic mucosa t.\J) are separated Iron the subimtcosa (5) by the nnn.'iilr.ii* mucosae (ni). (It) I oltpaine pcl-thlcnnated biph-myl ingestion the hyrv'Tkn'.ic mucosal elands pcnctrjic the n-1;r! hi* mucosae to f.nm mucus filled c\sl* o', ifv Stibmucosa. Cells lining c\-t umovr t.-> area indicated by arrow (-) aic uivaif*x*d in' Viy>. 2. 1x40-. scale cpro*c>n '00 run). s< it \.< } vnt. P'1 of the glands predisposed to the devel opment of Urge mucous cysts. Glands of the fundic area which normally con tain a variety of secretory cell types consisted primarily of mucus-secreting cells. Widespread penetration of the mus* ctilaris mucosae and invasion of the submucosa by the mucosal epithelium (Fig. t) 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 submuccsa. Other cells assumed a glandu lar pattern. Serial sections of (he sub* mucosal cysts demonstrated stratified arrangements of proliferating epithelial cells which penetrated the basal lamina and.invaded the surrounding connective tissue 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 sir.c and shape to the nuclei of the epithelial cells lining the cysts. Occasionally, ir regular hyperchtomic 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 to Use glandular and cystic changes was common. The increased ccllularity of the mucous glands with invasion of the muscularis mucosae and accompanying inflammation noted above is histologi cally described as a hypertrophic gastritis. The extension of the mucosal epithelial cells into the sobmucosa and the presence of irregular stratified ar rangements of epithelial cells within the submucosa are distinctly dysplaslic pat terns. The experimental concentration of biphenyls (300 ppm) within the diet which was sufficient to produce these conditions in subhuman primates in 3 months is about ten times the levels that have occurred in samples of milk (28 ppm) and of fish (35 ppm) re ported by the U.S. Food and Drug Administration (2). I bis concentration Is much less than the levels (hat have occurred in food products due to in dustrial accidents (2000 to 3000 ppm) O). The magnitude of the chronic ef fects which could be produced by PCDinduced hypertrophic gastritis is as yet undetermined. The nausea and vomiting following human consumption of I'CU's ate possibly a result of (he gastric irrita tions. Weight loss by the. experimental FP,,'TO. - '' :. X\ ::.........".?sa A?* ,V. * Vv , ' > v. i iu > V.N ; : v .V.'l '/wv `v&'m ,0 - ,-K ` :.v- , a. * - . H . ' *. . - '"-V. k-.'.u - .V|p,V ^ ` Va* r r- - ' [ V-: vj--a 9 ,,f 1 [Viy.. ,vl'' ' ! w I1 > *' 51 _ .; ' .) Fig. 2. Glandular epithelial cells that have extended from the mucosa into the sut^ mucosa encompass large cysts (C). In some areas (-*) the epithelial cells ate stratified and penetrate into the connective tissue of the submucosa. The cell nuclei of the stratified area is similar in sie and appearance to that of the simple columnar epithelium dial lines the remainder of the cyst (see inset). Serial sections of the tissue confirmed the stratified arrangement of the epithelial cells (x250, inset x640; sente represents 50 *m). . monkeys and human patients exposed 4o the PCB's may be related to gastri tis. Replacement of the parietal cells by the mucus-secreting cells which oc curred in the fundic glands of (ho more severely affected animals may re sult in achlorhydria and eventual pernicious anemia owing to the lack of intrinsic factor necessary for vitamin D|) absorption. Invasion of the muscularis mucosae and submucosa by the epithelial elements may lead to loss 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). Because interest in these environ mental contaminants is only recent, in vestigative efforts have nol yet deter mined the long-term carcinogenic poten tial of I'CB's and PCT's. T he associa (ion of chronic irritation with cancer, particularly of the stomach, cervix, oral mucosa, and bronchial epithelium, is well documented. These dvsplastic cel lular abnormalities of the hypertrophic gastric mucosa arc 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 clarifica tion of die carcinogenic potentials of these compounds. J. R. At t.EN D. II. Norihck Department of Pathology, Medical School, and Regional Primate Research, Center, University of Wisconsin, Madison 52706 Rtftrtnrri and Nolti 1. R. W. Ritebroiifh. (*. RIcche. D. D. Prakull. S. O. Human, M. N. Kli.cn. Nome 120, 1008 (1961). 2. A. C. Kolbrc, Cnvlren. Health rtnpret. I, 15 (1972). 3. O. I--. Piirt. /AW., p. 55. 4. A. R. Yobs, tbU,, f. 79. 3. M. Kurauuoc, T. YotMmura, i. MauutaVa, A. YamacuthJ, Ibid., p, 119. 6. ;. O. V. lbId., p. 101. 7. I). It. Norback and J. R. Allen. Ftd. /'roe. 29, IIS (1970). I. M. Nlthiruml, A/eh. Environ. 1/eallh II, <20 0*70). 9. !. L. Lincer and D. D. PeakaU, Nature ill, TBS (1970). ID. M. Ogawa, Ftikuoka-ttaku-ZotiUl. il. 74 (1971). II. ). Hitman and H. C. Cecil, l. AfHe. f o>J Chew. 1*. )U< (1970). J2, J. II. Alim ard I.. A. Cariicm, Amer. i. Vet. Ret. 31, 1)13 (1967). I). TT.il >oik wat mpponed by Kill jran:t 1.500472 and RR00167, and Wiwmin Sea Grant Program. 20 Ociohcr 1972 HOMS 0 8 2 6 0 0 2 FLDKUARY 1973 499