Document mwxGOb16Q3bVYDMJ0818p4LO

i * * Health & Baynards House 1 Chepstow Place Safety London W2 4TF 7elephone 01 229 3456 Executive ext i Dr J Stafford Division Manager Health & Environment Protection ICI Limited, Plastics Division P 0 Box No 6 Bessemer Road Welwyn Garden City AL7 1HD fcjt~ Your reference Our reference I/MS/4O6/225/78 6 October 1978 PVC DUST Xhank you for sending me a copy of Waxweiler's report on PVC dust and the item from Tox-Tips* Both will be discussed at the next tri-partite medical meeting which should take place in late November* Dr Elliott Harris the head of the Division of Bio-Medical and Behavioural Science, NIOSH, was here on Tuesday 3 October and told me that the study by Dr Trent Lewis had been completed and no evidence of carcinogenicity or pneumoconiosis had been found in any of the animal species* X enclose copies of the reports given to roe by Dr Harris* * Yours sincerely D B Douglas Deputy Director of Medical Services ccj Dr R Owen Dr P:S Fairweather 00 s c N BFG17394 v FVC Chronic Inhalation Toxicology Study Polyvinyl chloride (PVC) is widely used in various forms. Rigid PVC is used for tubing and fittings (insulation material and drainage pipe), foils, films and sheeting (packaging, recording tapes), profiles (blinds, window frames), tiles, sound records, and fibers. Flexible K PVC is used for cables, foils (decoration, roof covering), tubing, artificial leather, flooring, foam rubber, paint, varnish (lacquer), and toys. Reports of pulmonary dysfunction and pneumoconiosis in PVC workers and dust exposed animals point to the need for further studies on the toxicological properties of the polymer. Also, cases of still-births, } miscarriages and malformations among workers engaged in the polymeriza tion of vinyl chloride have aroused great Interest in the toxicological properties of PVC. Since PVC is a fine volatile dust, pathogenic effects of the lungs may be anticipated. B. F. Goodrich Company is a supplier of resins for vinyl dispersions using the trade name "Geon." The dispersions are fluid suspensions of special fine particle-size polyvinyl chloride resins in plasticizing liquids. When the system is heated to about 148 to 177C (300 to 350F), fusion (mutual solubilization of resin and plasticizer) takes place. The dispersion turns into a homogeneous hot melt. When the melt is cooled below 30 to 60*C (122 to 140*F), it becomes a tough vinyl product. The term "plutisol" Is used to describe a vinyl dispersion which contains no volatile thlnners or diluents. Plastisols often contain stabilizers, fillers, and pigments along with the essentials, dispersion resin and liquid plasticizer, but all Ingredients heve very low volatility under the processing and use conditions. Geon 121 Is a high molecular weight resin. It has been the standard of the plastisol industry for over 23 years and is an excellent resin for starting point formulations. Currently, it is being used in dip, slush and rotational molding, spread coating, foam coating and molding, crown and jar seals, and caulks and sealants. In light of the relationship unequivocally established between occupational exposure to vinyl chloride monomer and liver angiosarcoma, and the concern expressed on potential risks to human health from exposure to polyvinyl chloride (FVC) dusts manufactured and used from polymerization of the vinyl chloride monomer, DBBS in FY'75 in Its project plan on "Chronic Exploratory Toxicology Studies and Test of Validity of Industrial Air Standards" proposed an inhalation exposure study with PVC dust. Actual exposures to a representative material (B. F. Goodrich Company, Geon 121) began In February 1976 utilizing three species of animals -- monkey, guinea pig and rat--- a 6-6-1/2 hours per day, 5 days per week exposure regimen, and at a 10 mg/m respirable PVC dust concentration. Exposure duration was for 22 months. The following table summarizes the above data. 4t "l BFG17395 21984003 S e le c te d Data fro m PVC C h ro n ic In h a la tio n E xposure S tu d y (Geon 121) rH 0) rt n pw rH (0 i s o < a H O oq a a rt 13 c 0) jj c M o " o CO rH O' tr\ ID o rt tH H fv rs rt * rH ooO ao o rt rHk r sO CO rt rt N rH rH V 00 cu eo o d to U-l o> o S n C AC e in N cr> I1 tr> rt I u > Cl* o c(r0t co o X rt e AC a oo v - ooo rH H rH rt M p no w> ou CX M p Vi o o- X w rt M U-l v> O o> cx <o oc kXl CJ w u kJ a rt x? dw rt > 3 co H CO <N CO CH rt rH rt N rt rH rt rt vO -rt rt <r <H N o O' \D CTv r- r n r-> rH O a k. o=) kl w oC oV kJ rt D o rt .M oO SG a X u M h rt rt rH 43 8 o oo H rt OO oOO rH rt CO t* rH r>t% Or rt<\} M d 4Lr C H <3 o rt: r l b be BFG17396 21984004 > f. Particle size analysis of collected exposure chamber samples indicated that the generated PVC dust was of a geometric mean diameter of 0.53wm vfVh more than 99% of the sampled particles below 5.0um, 82% below t 1.0pm. The manufacturer*s specifications data states a particle size f range for Geon 121 of between 0.3 and 1.5pm. Exposure System: Chambers used in the study were five feet square, stainless steel, and featured a dynamic airflow system of 40 cubic feet per minute under a negative chamber pressure of approximately 0.2" H0. The PVC aerosol was generated by means of a Wright Dust Feed Mechanism l and the dust dispersed Into the chamber at a rate sufficient to maintain the desired 10 mg/m* concentration. Gravimetric analyses were made four times per day on collected membrane filter samples for total dust con centrations, and once per day for respirable dust (10-plate horizontal elutrlator sample). Biological response data evaluated from the exposed and control animals at time of serial sacrifice/evaluation included: Blochemlcal/Clinical Chemistry (Guinea Pig, Rat only): (SCOT, SGPT, alkaline phosphatase, gamma glutamyl transpeptidase, total protein and serum-protein electrophoresis). No significant differences were indi cated in rats for any parameter. Guinea pig data shoved controls with higher SGOT, SGPT, and alkaline phosphatase. It was concluded that no extensive liver damage was detected by any of the liver clinical Indicator tests used. However, a sizable amount of liver damage must occur before these tests would indicate abnormalcy. One cannot conclude that there is no liver damage; but only that there is no extensive liver involvement. Pathology (All species): No significant alterations in liver tissue. The only contribution of the Inhaled PVC dqst deposition and retention to pulmonary tissue morphology was aggregation of PVC-containing macro phages (refer to attached pathology reports and to report on Amorphous Silica exposed and control monkeys). Pulmonary Function (Monkey only): Fasted, exposed and control monkeys were tested for pulmonary function one day following their last exposure. Evaluations were accomplished through use of a variable pressure, wholebody plethysmograph. Tests evaluated were: Total lung capacity (TLC); vital capacity (VC); inspiratory capacity (IC); residual volume (RV) divided by total lung capacity (RV/TLC); forced expiratory volume in 0. 5 seconds (FeV 0.5); forced expiratory volume in 1.0 seconds (FeV 1.0); peak expiratory flow (PF); maximum mid expiratory flow (MMF); maximum expiratory flow volume curves (MEFV) at 50%, 25% and 10% of vital capacity; resistance; and compliance. A summary of the extensive pulmonary function evaluations indicated some signs of loss of lung recoil pressure, probably a result of the animals' aging process. In most cases differences were noted during the second and third testing periods (exposure months 6 and 14) and were Indi cative of some small airway obstruction. At this time, however, these differences were not statistically significant. At the last evaluation (month 22) compared with baseline (pre-exposure) data there were no signi ficant differences for any parameter tested. Impairment of respiratory function does not appear to be indicated under the conditions of this 6tudy from exposure to respirable PVC dust. Attachments BFG17397 21984005 , fy 1 1/J Vi. Wi.V i-^ XTI CfcNTF.R l|)ll IMSI.AM- CONI KOI. NATIONAL INSTITOYK TOK <K t OPA'I IONAI. SAIlilY AND IITAI OI TO Chief, USB THROUGH: Chief, Pathology Section DATE: Kay 5, 1977 FROM 1 Veterinary Pathologist, Pathology Section : SUIU1-CT: Pathology Repoxt on Rats Exposed to PVC --I 'I - .i Male rats were exposed by lnhala|loQ to polyvinyl chloride (PVC), respirable concentration 10 mg/m , for 6 hours/day for 5 days/wcek for a period of 12 months. The animals were sacrificed immediately after 12 months of exposure to PVC. The following tissues on each animal were saved at necropsy for histopathology evaluation: lungs, liver, heart, spleen, kidney, pancreas, adrenal, thyroid, testis, and urinary bladder. The histopathology evaluation was performed on a total of 121 (exposed 57, control 64) male rats. 1.1 Rats exposed to PVC 10 mg/m for 6 hours/day for 5 days/week by Inhalation. Path. Accs. No.: 76-1329, 76-1337, 76-1338, 76-1340 to -1393. Gross pathology: Lungs: Multiple white foci of varying size either in one or more lobes of the lungs were seen in 76-1337, -1338, -1344, -1345, -1347, -1348, -1350, -1353, -1354, -1363, -1367, -1369, -1373, -1379, -1385, and -1387. "Abscess" was seen in the lungs of each of 76-1346, -1351, -1352, -1363, and -1378. "Tumor" measuring 1.5 x 2.0 cm and weighing 2.90 gra Liver: was seen in 76-1375. Enlarged dark red liver was seen in 76-1337. Kidney: Small mineralized areas (stones) were seen in the kidneys of 76-1363 and 76-1366. Pituitary gland: Enlarged (10X) pituitary was seen in 76-1338. HistopatholQRy: Lungs: The lesions cowroonly associated with the chronic murine pneumonia (bronchiectasis, peribronchial, and perivascular accumulations of lymphocytes, .Coca] chronic active bronchitis and bronchiolitis, focal atelectasis) were seen in all rats. Vascular (arterial) wall mineralization was seen .in all rats. Focal Intense macrophage accumulations (solid sheets), sometimes displacing the normal structuvcs, were uccn. Most of these macrophages had varying size globular to spherical structures in the cytoplasm (foam cells). 21984006 *ry- BFG17398 WH * I 3 Chief, BSB These dense conglomerations of macrophages were occasionally associated with mild blue staining (mucin?) fluid material. The above-mentioned macrophages or macrophages surrounded by fluid when accumulated at the periphery of the lung probably Imparted the appearance of "white foci" grossly seen in the lungs. The intracellular, material in these macrophages was probably parti cles of the rVC. No birefringence was seen among these. Dr. Stettlcr and Mr. George Machay informed me that these, indeed, were PVC particles, based j on electron probe analysis of some lungs from the rats exposed to PVC by inhalation as well as by intravenous injection. The macrophage accumu lations apart from physical displacement of the lung parenchyma do not seem to bestow aiiy dele terious effects on these rats. No alterations (hyperplasia, etc.) of the alveolar or bronchial epithelium attributable to treatment were seen in these, rats. Tracheobronchial lymph nodes (TBLN): Macrophage accumulations as seen in the lungs were seen in the medulla and cortex of all the TBL.Ns examined. Reactive hyper plasia of germinal centers was also seen. Liver: Mild fatty infiltration of hepatocytcs was seen in 76-1338. Extra medullary hematopoiesis (mild) was seen in 76-1364 and 76-1371. Spleen: Macrophages containing yellow granular material in the cytoplasm and extramedullary hematopoiesis ware- seen in all the spleens examined. Heart: Mild focal myocarditis was seen in 76-1337, -1363, and -1377. Kidney: Multifocal mineralized areas of the tubules or the transitional epithelium of the kidney pelvis were seen in 76-1348, -1353, -1356, -1363, and -1366. Focal tubular dilatation, focal tubular epithelial degeneration and regeneration and mild lymphocyte accumulations were seen in 76-1351, -1356, -1357, -1363, -1370, -1376, -1381, -1382 to -1384, -1387, -1388, -1390 to -1392. Pancreas Mild hyperplasia of the Islets of Langerhans was seen in 76-1355, -1361, -1363, -1364, -1367, -1368, -1370 to -1372, -1376, -1377, -1379 to -1381, -1385 to -1389, and -1391 to -1393. Adrenal: Moderate fatty infiltration of the epithelium of the cortex was seen in 76-1341 to -1344, -1348 to -1350, -1369, -1370, -1378, and -1381. An adrenal cortical adenoma was seen in each of 76-1365 and 76-1371. A phoochromocytoma was seen In 76-1358. 2 A00F96TZ MR? BFG17399 Chief, USB 3 Thyroid: Cyst(s) containing keratin was seen In 76-1337, f -1338, -1341, -1342, -1345, -1346, -1353, -1355 to -1357, -1360, -1361, -1364, -1365, -1370, -1372, -1374, -1375, -1379 to -1382, -1388, -1391 to -1393. Testis: Vessel (artery) wall mineralisation was seen In 76-1358, -1378, -1385, and -1390. Mild hyperplasia of interstitial cells and atrophy of seminiferous tubules were seen in 76-1347, -1353, -1358, -1361, -1365, -1370, and -1378. Lymph node: Chronic lymph adenitis was seen in 76-1375. The lymph node was adjacent to a major artery suggesting It to be a mediastinal lymph node;. Pituitary: A chromophobe adenoma was seen in 76-1338. All the other organs examined were unremarkable. 1.2 Untreated Male Rats Path. Aces. No.: 76-1394 to -1431, 76-1510 to -1520, 76*1523 to -1537, 76-1539 to -1548. Gross pathology: A cataract of the right eye was seen in 76-1396. Consolidation of lung lobes was seen in 76-1395, i -1400, -1416, -1527, -1530, -1537, -1540, -1546, and -1547. Brown discoloration (76-1405) and an abscess was seen in- the lungs (76-3418). A nultiloculated mass 2.5 x 3.0 cm was seen attached to mesentery in 76-1427. Renal calculi were seen in 76-1518. Hlstopathology: Lungs: The morphological changes associated with the chronic murine pneumonia and pulmonary vascular wall minerali sation as seen in 1.1 were seen in all rats. Macro phage accumulations of far lesser degree in Intensity were seen in all rats. These macrophages did not congregate in a solid sheet as seen in 1.1. The cyto plasm of most of these macrophages contained granular eosinophilic material. No alveolar or bronchial epithelial hyperplasia was seen in any rat. TBLN: Chronic reactive hyperplasia was a common finding in all rats. Liver: A single cyst was seen in each of 76-1397 and 76-1399. Spleen: The changes seen were similar to those seen in 1.1 In all rats. Heart: Mild focal myocarditis was seen in each of 76-1401, -1402, -1405, -1407, and -1415. Pancreas: Mild hyperplasia of endocrine elements was seen In 76-1395 to -1399, -1402, -1404 to -1410, -1414 to -1418, -1420, -1421, -1424 Co -1426, -1428, -1429, -1510, -1511, -1514, -1515, -1518 to -1523, -1532, -1539 to -1542, and -1545. 21984008 BFG17400 Chief, BSB 4 Kidney: Tubular epithelial degeneration and regeneration, occasional tubular dilatation and focal mild lympho cytic accumulation were seen in 76-1394, -1396, -1397, -1399, -1401 to -1403, -1405, -1409, -1412, -1417 to -1419, -1421, -1422, -1425, -1431, -1515, -1524, -1527, -1534, -1546, and -1548. Focnl mineralisation of tubular epithelium mul/or the transitional epithelium of the renal pelvis was seen in 76-1518, -1527, and -1533. Adrenal: Adenoma of the adrenal cortex was noticed in 76-1400, -1518, -1523, and -1544. Phcochromocytoraa was seen in 76-1548. Moderate fatty infiltration of the cortex was seen in 76-1410 and 76-1544. Thyroid: Cyst(c) containing keratin was seen in 76-1395, -1397, -1399, -1402, -1403, -1406, -1410 to -1412, -1416, -1417, -1419, -1420, -1422, -1423, -1425 to -1427, -1429, -1510, -1512 to -1515, -1517, -1519 to -1527, -1529, -1530, -1532 to -1534, -1536, -1541, -1543 to j -1548. Testis: Atrophy of seminiferous tubules and Leydig cell hyper plasia was seen in 76-1395, -1400, -1514, -1516, -3533, -1541, and -1548. Vessel (artery) wall calcification was seen in 76-1398 and 76-1533. Focal moderate mineralisation of seminiferous tibules was seen in 76-1418, -1510, and -1517. Eye: 76-1396: Ketin.il atrophy - .unilateral. Adhesions between the retina and lens with dystrophic calcifi cation at some foci. The lens protein was well oriented with occasional basophilic bodies, probably nuclei from decidual lens cells. The calcific deposits coupled with i the hyallnization of sclera imparted the opacity to the lens; cataract seen grossly. Hass: 76-1427: Granuloma of mesenteric fat. Comment: For comparison, this comment shall Include rat and guinea pig data. Both the rats and the guinea pigs exposed to PVC by inhalation exhibited the presence of PVC particulates in the pulmonary macrophages, . although the pattern of macrophage accumulation between the two species differed. There was no inflammatory or any other deleterious effect scon * in'the lungs of these animals that could be attributable to PVC inhalation. The incidence of pcrivAacular lymphoid aggregations in the lungs Of guinea pigs was similar in both exposed and controls. The presence of bony spicules in the lungs of exposed and control guinea pigs was observed. The patho genesis of these iwo conditions is not known (Thompson, S. W., Hunt, R. D. ct al: Am. .1. Path. 40:507-517 (1962); Kaufman, A. F.: Lab. Anim. Caro 20:1002-1003 (1970)) and is worth exploring ns N10SH uses guinea pigs as 21984QQ9 BFG17401 Chief, BSB 5 k one species of animals in biological experiments. The nephrocalcinosis seen in the exposed and control guinea pigs may be related to diet (J. C. Woodard: Am. J. Path. 6.5:253-268 (1971) nnd 65:269-278 (3.971)). Corollary to the above observation was the finding of invariable fatty infiltration of exocrine and cndQcrine elements of the pancreas in both the exposed and control guinea pigs and the hyperplasia of islets of Langerhans seen in both the rats and the guinea pigs employed in this experiment. In addition, the vascular wall calcification in the pul monary vessels of rats is disturbing. All of these "incidental" findings strongly suggest that these animals had metabolic problems probably related to the animal diet. The changes seen in the testes of rats were non-specific and probably not related to treatment. The incidence of neoplasms in the adrenals of rats is within the normal range observed for Sprague-Dawloy rats of this age. S' "> i , (, v oramineni, D.V.M. 21984010 . BFG17402 MEMORANDUM TO Chief, ETB Through: Director, DBBS __ , Chief, BSB DEPAKiMbNi' OF HEALTH, EDUCATION, AND WELFAK1 PUBLIC HEALTH SERVICE CF.NTER PO* DISEASE CONTROL NATIONAL INSTITUTE FOR OCTUPA1 (ONAt SAITTY AS`f> HFM m DATK: September 6, 1978 { ^ from 1 Research Veterinary Medical Officer SUBJECT: Pathology Report on Monkeys Exposed to PVC Ten male Cynomolgus monkeys were exposed to PVC at 10 mg/m by inhalation for 6 hours/day, 5 days/week for almost 22 months. Control male monkeys (10) were maintained In an open animal room i in their individual cages. The monkeys were killed within 48 hours after the final exposure. At the time of autopsy* tissues from the lungs (all lobes with trachea), thyroid, heart, tracheobronchial lymph nodes (TBLN), mesenteric lymph nodes (MLM), liver, spleen, kidney, urinary bladder, prostate, testis, stomach (pylorus), duodenum, pancreas, adrenals, and skin from the abdomen were saved for hlstopathology. 1.2 Control Monkeys Path. Accss. 077-2975, 77-2979, 77-2981, 77-2983 to 77-2986, 77-2991, 77-2993 and 77-2994. Gross and hlstopathology: See the pathology report on monkeys exposed to Silica-F. * 1.2 Monkeys Exposed to PVC Path. Accss. 077-2974, 77-2976, 77-2980, 77-2982, 77-2988, 77-2989, 77-2995, 77-2996, 77-2997 and 77-2999. Gross Pathology: Adhesions between the lobes of the lung and the thoracic wall were seen in 77-2980, 77-2995 and 77-2997. Multiple black areas were seen in the lungs of 77-2976, 77-2980, 77-2982, 77-2988, 77-2989, 77-2996, 77-2997 and 77-2999. En larged end black MLNs were seen In 77-2974 and 77-2976. Hlstopathology: Lung: Macrophages with anisotropic particles as In the controls were similarly present in all these monkeys. Admixed with these macrophages were other macrophages with spherical material (PVC) of varying size in the cytoplasm. About 15X of the total macrophage aggre gates (macules) in 77-2997, 77-2988 and 77-2980 contained black to brown anisotropic particles of the same degree of deposition as In the controls. In the rest of the PVC exposed monkeys 20 to 22Z of f i Z1984011 *<?4 BFG17403 F # i "1 a i ) I ;-1 -i Chief, ETB 2 the macules had these black to brown particles. A total of 110 macrophage aggregates were seen at 25X magnification In most of the lungs. The diameter of many of these aggregates varied from 100 to 200y while the largest, present In the alveolar region, measured 475y. The macro phage aggregates were present in the alveolar wall6, alveoli, partially obstructing the alveolar lumens. They were also present around tertiary bronchioles and in some alveolar ducts without causing observable obstruction* A few places showed submucosal accumulations with no polypoidal projections. With phase contrast illumination these macrophage accumulations appear as blue aggregates. This tinctorial character is distinct from the macrophage aggregates seen in amorphous silica (F, G and P) exposed monkeys. Focal hyperplasia of type IX cells was present in 77-2989. Smooth muscle hyperplasia was seen around blood vessels and alveolar walls in 77-2996. Acute bronchopneumonia was seen in 77-2986. Plant material was present In a bronchus in 77-2999. Multiple gaint cells away from the plant material were seen in the 77-2999. Hon-inflammatory arteriopathy as in the controls was present in all these monkeys. TBLN: As in the controls the medulla contained macrophages with anisotropic particles. In addition, other macro phages with cytoplasmic material (PVC - blue In color - see lung) were present. Together, these macrophages replaced most of the medulla of the TBLNs in all monkeys. Liver: Diffuse fatty infiltration of the hepatocytes was present in 77-2982 and 77-2996. Kidney: Multifocal calcification of cortical tubules was seen in 77-2995. MLN: See the controls. The other tissues examined were unremarkable. Comment: A slightly higher number of macrophage aggregates containing black and brown blrefrlngent particles were seen in PVC exposed than in the control monkeys. The pattern of distribution of the macrophage accumulations in the PVC exposed and the amorphous silica (F, G and P) exposed monkey lungs and the TBLNs was similar. The macules were smaller in size in PVC exposed than those seen in the amorphous silica (F, G and P) exposed monkeys. The monkey lung reaction suggests that it may be a 2 1 0 ^ 8 6 TZ BFG17404 Chief, ETB 3 non-specific one, inasmuch as these materials (PVC and amorphous silicas-F, G and P) show diverse chemical composition. The second paragraph under "Comment11 in the pathology report on monkeys ex posed to amorphous silica-K also applies here. The Influence of the brown and black particles on the biologic effects of PVC are hard to define but should be carefully considered. The only contri bution of the inhaled PVC dust deposition and retention to pulmonary tissue morphology was numerous aggregations of PVC-containing macrophages. Choudarl Kommlneni, Ph.D., DVM 21984013 BFG17405 ^MEMORANDUM ' DliPAKTMHNT 01; IIIALTII, EDUCATION, AND WI-U'AKh I'UHI Ks IIHAI Hr SI KVK K CI'KU K l-OK IIINFANIi CONIHOI national iNsmtm: iok ocmh'aiionai. .saimv and iiiaiik TO Chief, BSB lUROUGH: Chief, Pathology Section s DATl?: May 10, 1977 J- *fKOM Veterinary Pathologist, Pathology Section UBJECT: Pathology Report on Guinea Pigs to PVC Male guinea pigs were exposed by^inhalation to polyvinyl chloride (PVC), respirable concentration 10 tug/m , for 6 hours/day for 5 days/week for a period of 12 months. The animals were sacrificed immediately after 12 months of exposure to PVC. The following tissues on each animal were saved at necropsy for histopathology evaluation: lungs, liver, heart, spleen, kidney, pancreas, adrenal, thyroid, testis, and urinary bladder. The histopathology evaluation was performed on a total of 75 (exposed 36; control 39) male guinea pigs. J 2,1 Guinea Pigs exposed to PVC 10 mg/m* for 6 hours/day for 5 days/ week by inhalation. Path. Accs. No.: 76-1432 to 76-1467. Gross pathology; Yellow specks were seen in the lungs of 76-1434, -1436, -1459, and -1464. Consolidation of lungs was observed in 76-1435, -1437, -1439, and -1449. Small areas of necrosis in the liver of 76-1443 were Been. Mesenteric fat necrosis was found in 76-1438 and 76-1441. \ Histopathology: Lungs: All guinea pigs exhibited moderate amount of eosinophilic serous exudate mixed with mild to moderate numbers of epithelial cells (decidual showing varying stages of de generation) in the bronchial lumenu. Another common find ing among all guinea pigs was the presence of multiple aggregates of lymphocytes. Most of these lymphoid aggre gates were oriented around or near small arteries or veins, thus giving an appearance of lymphoid follicles. The Interstitium of all the lungs showed numerous macrophages. These macrophages contained spherical to globular hollow structures in the cytoplasm. These macrophages did not aggregate in the same fashion as those seen in rat lungs (1.1). Plant material with or without associated inflam mation was seen in bronchioles of 76-1432 and 76-1435. Bone formation (small spicules) in alveolar area was seen in 76-1434, -1435, -1438, -1446, -1452, -1453, -1455, and -1456. Focal atelectasis was'scon in the Lungs of all guinea pigs examined. 21984014 Wf BFG17406 i I* ' hf \ 4 1 t Chief, BSB 2 Liver; Mild fatty infiltration of hepotocytcs was soon In 76-1432, -1441, and -1467. The histology slides from 76-1443 did not show any hepatic necrosis. Search for liver tissue with necrotic areas from "wet tissue" waa not fruitful. Heart: Focal mild myocarditis was seen in 76-1441, while 76-1449 showed focal mineralization of myocardial muscle bundles. Spleen: Macrophages with yellow granular pigment in the cyto plasm were seen in all guinea pigs. Kidney: Multifocal mild mineralization of tubular epithelium . waa seen in 76-1432, -1437 to -1448, -1450 to -1460, -1462 to -1465, and -1467. Pancreas: Fatty infiltration of the endocrine and exocrine ele ments was seen in 76-1439, -1442, -1444, -1447 to -1456, -1458 and -1461. Fatty infiltration of only exocrine elements and moderate hyperplasia of the endocrine elements were seen in all guinea pigs excluding the ones given above. Adrenal: Yellow granular pigment in the cytoplasm of the cortical epithelium was seen in all guinea pigs. Focal mild mineralization of the cortical epithelium was seen in 76-1435 and 76-1455. Urinary bladder: Mild focal hyperplasia of the transitional epithelium was seen in 76-1444. Mineralization of sur face epithelial cells was seen in 76-1452, -1453, and -1462 to -1465. 2.2 Untreated Ruinea pigs Path. Accs. Ho.: 76-1470 to 76-1508. Gross pathology: Consolidation of lungs was seen in 76-1488, -1490, -1506. Small necrotic foci were seen in the livers of 76-1486, -1488, and -1491. A contracted kidney was seen in 76-1493. Necrotic fat (mass) was found attached to mesentery of 76-1475 (3.57 gm), -1477 (3x2 cm), -1480 (4.5 x 2.5 cm), -I486 (1.0 x 2.0 cm), -1494 (1x2 cm), -1495, and -1496. Histopatholonv: Lungs: The presence of eosinophilic fluid exudate with cellular debris and the lymphoid aggregation in all guinea pigs was the same as seen in 2.1. The intorstltium of all the lungs contained lesser number of macrophages than those seen in 2.1. The cytoplasm of those macrophages was granular and eosinophilic. Plant material with or without Inflammatory infiltrates was seen in 76-1468 and -1490. Bone formation in the alveolar region was seen in -1474, -1475, -1476, -1478, -1490,-1493, -1499, -1501, and -1506. Focal consolidation of all lungs was seen. 21984015 :mac BFG17407 Chief, BSB Liver: Fatty infiltration (mild) of hcpntocytes was seen in 76-1472 and 76-1478. Moderate hyperplasia of bile ducts was seen in 76-1474. A mycloliposarcoma was seen in the liver of 76-1470. Spleen: Macrophages with yellow granular material in the cyto plasm were seen in all guinea pigs. Kidney: Multifocal mild to moderate mineralization of tubular epithelium was seen in 76-1470, -1471, -1473 to -1483, t -1487 to -1508. Pancreas: Fatty Infiltration of exocrine and endocrine elements . -1 was seen in 76-1470 to -1475, -1478, -1480, -1482, -1486, -1488, -1490, -1492, -1494, -1495 to -1497, i -1501, -1502, -1503, and -1507. The pancreas from the remaining guinea pigs showed fatty infiltration of exocrine elements and hyperplasia of endocrine elements. Adrenal: Yellow granular pigment in the cytoplasm of the epi thelium of the cortex of all guinea pigs was seen. Urinary bladder: Mineralization of the surface epithelium was seen in 76-1472, -1475, -1480, -1495, -1497, -1498, and -1504. Subacute cystitis was seen in 76-1470 and 76-1494. \ Mesenteric masses: 76-1473: Granuloma of mesenteric fat. Entrapped pancreatic exocrine elements were present. 76-1475: Granuloma of mesenteric fat. 76-1477: Thrombosis of veins with degenerative fat. 76-1480: Thrombosis of veins and degenerating fat. 76-1486: Granuloma of mesenteric fat; polarising y yellow material seen. 76-1494: Degenerating fat. 76-1496: Granuloma of mesenteric fat. Comment: For comparison, this comment shall include rat and guinea pig data. Both the rats and the guinea pigs exposed to PVC by inhalation exhibited the presence of PVC particulates In the pulmonary macrophages, although the pattern of macrophage accumulation between the two species 5 differed. There was no inflaramatory or any other deleterious effect seen in the lungs of these animals that could be attributable to PVC inhalation. i The incidence of perivascular lymphoid aggregations in the lungs of guinea pigs w<>8 similar in both exposed and controls. Hie presence of bony spi cules In the lungs of exposed and control guinea pigs was observed. The pathogenesis of these two conditions is not known (Thompson, S. W., Hunt, R. P. ct al: Am. .7. Path. 40:507-517 (1962); Kaufmnn, A. F.: Lab. Anim. Care 20:1002-1003 (1970)) and is worth exploring ns NI0SH uses guinea pics as one species of animals in biological experiments. The ncphrocalcinosis seen in the exposed and control guinea pigs may be related to diet (J. C. Woodard: Am. J. Path. 65:253-268 (1971) and 65:269-278 (1971)). Corollary i 21984016 \ BFG17408 "PLASTICS division NOTE ON A TELEPHONE CONVERSATION WITH OK M N JOWSON OF BF GOODRICH, 20 OCTOBER 1978 PVC DUST - NIOSH STUDIES Dr Johnson 'phoned to say he hod now hod a talk with Dr Trent Lewis of NIOSH on the 3 mammal study. Dr Lewis emphasised that this was in no sense o carcinogenicity study. It was a study oimed at ascertaining about pulmonary function and fibrosis. Dr Lewis was happy with the outcome of the work in that nothing happened and there was nothing to comment on the subject of pulmonary function and fibrosis. He thought the study was totoiiy unsuited to gauge carcinogenecity. In Dr Lewis's view an inhalation study of PVL dust on animals to demonstrate carcinogenicity is a very difficult undertaking. He would be very unwilling to tackle it unless there was something equivocal in the epidemiology that needed to be resolved. Even then he would advocate expanding the epidemiology to get a more positive answer. If there is a positive answer from the epidemiology no amount of animal work would moke any difference and again he stressed that dust inhalation tests for corcinogenicity on animals are long, tedious, difficult and uncertain. J Stafford Division Manager Heolth & Environment Protection JS/MJE/DSO-107 23 October 1978 VxC*v GO- 21984018 Circulation Dr W G F Adams Dr D P Duffield Dr G Pigott Dr B W Duck Dr N Shorratt Dr P Grosso Dr J T Carter Dr D W Plester Dr G Poddle Dr K $ Williamson Dr I F H Purchase Sir C Lawrence-Jones Dr F W Best Nr G J Sleddon Mr W Adams Mr R Hards Mr P H H Sharrock Mr T L Phillips Mr B N P Hutchesson Mr H M Clayton Mr T W Moffitt Dr L de Boer Dr J G Kammuller Mr J C Thomas Mr M 8onnefoy Dr T Garlanda Dr M N Johnson Dr T R Torkelson Mr R N Wheeler (Jr) JS (2) Dr R E Davies, ICI Australia Mr K H White, Duperial SAIC Chief Medical Officer, AECI BFG17410