Document YjgwOn2DGZXjaYdD5VrVLnY60

AFFIDAVIT OF WILBUR F. McNULTY Wilbur F, McNulty, having been duly evorn, deposes and says: - Hy name Is Wilbur P. McNulty and I live at 7835 S.W. 136th Avenue, Beaverton, Oregon. I am currently Chairman of the Laboratory of Pathology at the Oregon Regional Primate Research Center, 505 N.W. 185th Avenue, Beaverton, Oregon; I have held this poslcion for 13 years. 1 received a B.S. from Yale University in 1947 in mathematics and an M.D. degree in 1952, also from Yale University, l was an instructor in physiology for two years at the University of Pennsylvania, and received postdoctoral training in pathology at Yale University and the Armed Forces Institute of Pathology. I became a dlpiornate of the American Board of Pathology (Anatomy) in 1959. ' Except for four years in hospital practice, my activities have been exclusively in research and teaching. For several years, one of my (chief " x^V- Interests has been the diseases caused in rhesus monkeys by polychlorinateiT^y biphenyls (PCBs) and tetrachlorodlbenzo-p-dioxins (TCDD). Attached hereto as Appendix D 1$ my Curriculum Vitae, which includes my list of publications. Rhesus monkeys are among the most susceptible of all animals which have been tested, for the toxic effeces of FCBs. Male and female monkeys ranging in age from infancy through adolescence to adulthood were lethally^poisoned by PCBs--in this case, probably Aroclor 1260-fused in construction of monkey pens I in 1967 (Appendix A). Exclusive assignment of the cause of the disease to FCBs vat lacking, but the circumstantial evidence of highly characteristic pathology and identifiable FCBs in the livers of the dead animals was persuasive. My subsequent experimental work with FCBs will be summarized In the following paragraphs. In all experiments, the tested monkeys wore young (one to three |years) aulas, and the diet was a standard moist cake of. ground Purina monkey chow, vitamin and mineral supplements, banana, and water Into which waa homogenized Aroclor 1242 (one lot only: AD-73) at the designated concentrations. MOMS 087879 The purpose* of Che experiments were (1) to document qualitatively Che pathologic changes caused by PCBs and (2) to explore In preliminary fashion the dose range at vliich deleterious effects could be expected on chronic oral Intake. For these reasons, the numbers of animals used were too small for atatlstlcal dose-response analysis. Indeed, In view of the decreasing natural resource and escalating expense of monkeys, the destruction of a large number of animals to establish numerically accurate dose-responses, relationships would require careful justification. . The dietary concentrations used In different experiments involving 16 ' monkeys ranged from 3 to 800 ppm. All animals were fully examined postmortem, either after spontaneous death, or electlvely during development of disease or after a period of recovery on normal diet. The pathologic changes were the same at all dose levels and will be discussed below. In the first test, two monkeys each were fed diet with Aroclor 1242 at 100, 200, 400, and 800 ppm. It was soon apparent that these levels were far into the,toxic range. By the fourth week, all eight monkeys were depressed, eating poorly, aqd losing weight. Some vomited convulsively. Hair was lost from the head and trunk, the faces were edematous, and the eyelids red and swollen. One monkey at 100 ppm died on the 27th day. Subsequent deaths are recorded In Appendix B. Because of the high toxicity of this range of doses, normal diet was relnstituted on the 40th day. The order of death suggests that tha toxicity of diets containing 100 ppm Aroclor 1242 or more was so high Chat It was independent of dose. In Appendix B are also listed the estimated cumulative doses, based on e normal intake of 50 gm diet per kilogram of body weight per day; these aatlmataa ere certainly high, since the monkeys ate poorly after the first two weeks. . The tingle survivor (100 ppm) was clinically 111 for over a year, with failure to gain, depressed activity, and conjunctivitis. Abruptly, he recovered, end 20 months after the PCB exposure of 40 days ha was killed for pathological survey. mons oavaao ' A second experiment Included one animal each at 0, 3, 10, 30, and 100 ppm. For six mntha, at Intervals of one month, biopsies of Che wall of the fundus of the stomach were obtained at laparotomy. The order of death correlated Inversely with Che dietary level In this dose range. It should be emphasized that death occurred in eight months at only 3_gn. The contribution of the repeated abdominal surgery to illness and death is difficult to assess; the control, at least, remained in good health for the six months of biopsies and thereafter. The first recognition of clinical illness, as judged by depressed behavior and appetite, red and swollen eyelids, facial swelling, and rough, ragged appearance of the hair coat was as follows: 100 ppm - 50 days; 30 ppm - 60 days; 10 ppm - 60 days; 3 ppm - indeterminate. ' All animals In both experiments showed the same findings at autopsy. Independently of the dose. These changes were conversion of all secretory cell |types of the stomach to mucous cells, growth of mucous glands into the muscular wall of the stomach, multiple ulcers in the stomach, atrophy of the thymus gland, and either disappearance of sebaceous glands or conversion of these glands to keratin cysts, particularly in the eyelids. .The livers were enlarged but showed no consistent changes by light microscopy. In Appendix C is an illustration of the stomach in the 3 ppm monkey. The earliest changes seen in the mucosa of the stomach in the serial biopsies were as follows: 100 ppm - 6 weeks; 30 ppm - 6 weeks; 10 ppm - 15 weeks 3 ppm - IS weeks. The control monkey showed no changes; the repeated surgery alone did not affect the mucosa. In a third experiment, Intended to provide more data on the time of appearance and race of development, of. the principal pathologic lesions, three young mala monkeys wort killed for complete autopsy after eating diet with Aroclor 1262 at 10 ppm .for 30, SI, and 6S days. At 30 days, no microscopic laalons ware recognisable, and the liver and thymus were normal in size. At HONS 0S78B1 45 days, tha stomach was normal, but the liver was somewhat enlarged and sebaceous'glands In the eyelids showed early keratinization. Ac 65 days, * mucous change in the stomach was advanced; the sebaceous glands, in the eyelids and on tha face were markedly keratinized, the thymus was markedly atrophic, and the liver enlarged. There is, however, wide Individual variation in response to PCB intake; an animal currently eating Aroclor 1242 at 10 ppm shows only equivocal clinical signs and minimal gastric mucosal change (biopsy) at 77 days. * The two animals which survived the first high-level short-exposure |(,v* experiment for a year or more both had a new lesion: multiple cysts In the jaws surrounding the crowns of unerupted permanent teeth. In the monkey which died at 382 daya (400 ppm), this condition was so extensive that the face was grossly deformed. The leelons in the stomach, sebaceous glands, and thymus were still severe, and total PCBs were still high in the liver. The clinically recovered monkey .(100 ppm) killed at 20 months had a normal stomach and thymus and partial return to normal of sebaceous glands. The cysts in the jaws were small and partly calcified, but permanent teeth which should have erupted at this age were still deep in the Jaw, and the permanent third molar had failed to form at all. PCBs in the liver had by this time declined to a low level. These experiments may be summarized as follows: Oral Intake of Aroclor 1242 contiatenCly caused disease with pathological manifestations in the stomach, sebaceous glands of the tkln, thymus, and llver--a disease which could be lethal, even at a dietary level of 3 ppm, if sufficiently prolonged. The characteristics of the disease were identical to chose Allen ("Response of the nonhuman primate to polychlorinated biphenyl exposure," Federation Proceedings, v. 34, pp. 1673 1679, 1973) has reported in monkeys fed Aroclor 1248, and to thoee eeen in. our animals spontaneously poisoned with e more highly chlorinated product, probably . Aroclor 1260. The lesions persisted for at lease * year after intake of PCB \ cessed and, In young animals, an Interference in the development of ceeth became evident month* after exposure. MOMS 087882 The following conclusions may be drawn: (1) Rhesus nonkeys, at least young males, are seriously poisoned by oral Intake of PCBs as low as 3 ppm In food. They appear to be 10 to 100 . times more susceptible than laboratory rats. . (2) Some of the pathologic changes caused by PCBs In rhesus monkeys are . different from those reported for other animals. In particular, the change In the stomach Is unique, and because this lesion involves alterations in the growth and differentiation in the cells of the gastric mucosa, it is ominous with respect to possible late ' development of cancer. (3) Because monkeys are closely biologically related to human beings, they can be expected to be better models for toxicity studies than laboratory rodents, with respect to both levels of susceptibility . and qualitative features of toxicity. This expectation 'is in part supported by the published descriptions of clinical illness in Yusho disease, the accidental PCB poisoning of over 1,000 Japanese. The * affected eyelids in these people closely resemble those of monkeys. Fortunately, few of the Japanese have come to autopsy, and gastric lesions have not been reported; however, gastrointestinal disturbances were a prominent symptom. Monkeys are expensive and difficult to handle, and they constitute a highly variable, outbred population. The kind of "clean"-experiments with large numbers of animals showing a narrow range of response which can be done with rats will probably never be possible with monkeys. Nevertheless, it is my conviction that the Information already available from Dr. Allen's laboratory and on a limited .scale from my own indicates that studies with monkeys have the moat relevance for assessing the danger to human beings of low level exposure to PCBs. . Many details of FOB toxicity resialn to be uncovered: the toxic ranking of the aiany possible homologs and. isomers, the Identification and toxicological MONb 087883 6 valuation of contaminants in commercial preparations, the identification and \. '' ` valuation of new compounds formed from PCBs by degradation in the open environment, and by metabolism in organsisms -- including man--with body burdens of PCBa, and the late effects, if any, of very prolonged, very low level exposure. For these investigations, nonhuman primates will be highly desirable, if not essential. Wilbur P. McNuLty 23 A.Subscribed as sworn to for me this day of 1976 -mC-- S' Notary Public f'-' K;';" "'-r; ' 5, ;s7s MOMS 007ad4