Document 0gpwkdd0wLvrG78k3kKBZgx3n

PO Sox No S nnnniimr Roed WSwyn Gardm CXy Hertfordshire AL71HD KfcCeiVD OCT 27 1978 Telephone Wetwyn Garden 23400 (SID Coda 07073) Taiei 264291 * N. whpi^^; Imperial Chemical Industries Limited Fram J Stafford Dlvlaloa Nui(fr Heel IffCfBMfllitnnaent Protaction Plastics Division DEC 07 1978 See Circulation Below r.N, WHEELER, JR. Cepieete TO: SPI VINYL SUBCOMMITTEE FROM: W D Davis/R N Wheeler November 28, 1978 Your raf. PVC HOST Our raf JS/AXS/D60-107 Tal aat 3162 Data 17 October 1978 Toe nay eara to see the attached latter aad NI06B report I hare received froa Dr Douglas of DUS. This report aaaea reassuring bet I vould unloose the opialoe of our Medical Coonittee vho have bean considering hoe to design a good PVC duct inhalation study. Has the need for such a study dleappeared as a result of ths NIOSH work? Dr M N Johnson of B 7 Goodrich, when he saw an on 9 October* knee of these results but ues critical that the rodent species were sacrificed at 12 souths (aonksys 22 aoaths). Dr Johnson thought that a veil conducted full life study on PVC dust in* halation should still be considered and the possibility of Transatlantic cooperation explored to derive both protocol and funding. Dr WOT Adans Dr D P Duffield Dr O Pigott Dr B V Duck Dr M Sharratt Dr P drasao . Dr J T Carter Dr D V Plaster Dr 0 Paddle Or K S Vllllaasoo Dr If! Purchase Sir C Lawreaee Joaes Dr P V Best Mr C J Sleddon Mr V Adaas Mr B Hards Mr P H M Sharrock Mr T L Phillips Mr B N P Hutchesaoa Mr H N Clayton Mr T V Moffitt Dr ! de Boer Dr J O Eaanuller Mr J C Theaas Mr M Boanefoy Dr T garlands Dr M M Johnson Dr T B Torkelaon ffJfeB B.Whaaler (Jr)P JS (2) Dr B B Davies. ICI Melbourne Mr K H White* Duperial SAIC Chief Medical Officer* ASCI ' Ensi"U No 711019 Nifit*r*a 0"<r - Imp*.*! Howto. MilloonV London SNIP 3J9 vcc 010742 fJ i 5tfft i I v r*l Health & Safety Executive Bsyneids House 1 Chepstow Place London W24TF Ttleeiione 01*229 3459 Ml Dr J Stafford Division Manager Health & Environment Protection ICt United, Plastics Division P 0 Box No 6 Bessemer Road Welwyn Garden City ALT 1HD /JUr YBW ttformc* Out tefwcnc* 1/MS/406/225/78 Date 6 October 1978 FTC DOST Thank you for sending aa a copy of Haxweiler's roport on PTC dust and ths itsa froa Tox-Tips* Both will bo discussed at the next tri-partite asdical nesting which, should taka 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 aniaal species* I enclose copies of the reports given to as by Dr Harris* Yours sincerely hi*--**/ D B Douglas Deputy Director of Medical Services cc: Dr R Ower. Dr ?*S Fair-weather UCC 010743 PVC Chronic Inhalation Toxicology Study e P lyvinyl chloride (PVC) la widely used lo verlous ferae. Rigid PVC le used for cubing end flcclngs (Insuleclon necerlsl and drainage pipe), foils, files and attesting (packaging, recording capes), profiles (blinds, window frases), tiles, sound records, ssd fibers. Flexible PVC Is used for cables, foils (decoration, roof covering). Cubing, artificial leather, flooring, foam rubber, paint, varnish (lacquer), and toys. Reports- of pulmonary dysfunction and pneumoconiosis la PVC workers and dust exposed anlaels point to the need for further studies on the toxicological propercles of the polymer. Also, cases of stlU-blrths, miscarriages and malformations among workers engaged in the polymerisa tion of vinyl chloride have aroused greet interest in the toxicological properties of PVC. Since PVC Is a fine volatile dust, pathogenic ` effects of the lungs may be anticipated. B. ?. Goodrich Company is a supplier of resins for vinyl dispersions using the trade name "Geon." The dispersions are fluid suspensions of special fine partlcle-slse polyvinyl chloride resins In plasticising liquids. Uhen the system Is heated to about 148 to 177*C (300 to 35Q*F), fusion (mutual solubilisation of resin and plasticiser) takes place. The dispersion turns into a homogeneous hot melt. When the melt is cooled below 50 to 60*C (122 to 140*F), It becomes a tough vinyl product. The term "plastlsol" is used to describe a vinyl dispersion which contains no volatile tblnnera or diluents. Plaatlsols often contain stabilisers, fillers, and pigments along with the essentials, dispersion resin and liquid plasticiser, but all ingredients have very low volatility under the processing and use conditions. Geon 121 Is a high molecular weight resin. It has been the standard of the plastlsol Industry for over 25 years and Is an excellent resin for starting point fonailatlons. Currently, It Is being used in dip, slush end 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 (PVC) dusts manufactured and used from polymerization of the vinyl chloride monomer, OBIS la PY'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. P. 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 exposura regimen, and at a 10 mg/m respirable PVC dust concentration. Exposure duration was for 22 months. The following table suaanarizes the above data. 4 % ucc 010744 Selected Data from PVC Chronic Inhalation Exposure Study (Geon 121) Anteal Species Ko. per Croup Exposed "Control Duration of Exposure Calendar Exposure Exposure Days Days Hrs. Mean PVC Cone. Jt/n* Mean Range of Cone. */* * CT Values (e/a*-Hrs.) , Intended Actual Monkey Culnea Pig Rat 10 40 80 10 40 80 890 484 2818 10.8 4.65-9.23 28,160 30,510 379 243 1428 10.6 - 14,700 14,698 V* i1*1 378 244 1424 * 10.6 14,627 ,(*'f mm 14,640 o 4*0 cn r ~ " it r Particle size analysis collected exposure chamber saaples Indicated that the generated PVC dust was of a geometric mean diameter of 0.53um wfth eore than 99Z of the sampled particles below S.Oiia; 82Z below 1.0pm. The manufacturer's specifications date states a particle else range for Geon 121 of between 0.S and l.Sum. 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" K0. The PVC aerosol was generated by means of a Wright Dust Feed Mechanism and the dust dispersed into the chamber at a rate sufficient to mainteln the desired 10 ag/a* concentration.. Gravimetric analyses were made four times per day on collected membrane filter saaples for total dust'con centrations* and once per day for respirable dust (10-plate horizontal elutrlator sample). i Bioloalcal response data evaluated from the exposed and control animals at time of serial sacrlflcs/svaluation Includedt Blochaalcal/Cllnlcal Chemistry (Guinea Pig* Rat only): (SCOT, SOFT* alkaline phosphatase* gim glutamyl transpeptidase* total protein and serum protein electrophoresis). No significant differences were indi cated in rats for any parameter. Guinea pig data showed controls with . higher SCOT* SCPT* 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 abnormaley. One cannot conclude that there is no liver damage; but only that there is no extensive liver involvement. Patholoay (All species): No significant alterations in liver tissue. The only contribution of Che inhaled PVC dqst deposition and retention to pulmonary tissue morphology wes aggregation of PVC-contalnlng 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 lest exposure. -s Evaluations were accomplished through use of a variable pressure* wholebody plethysaograph. 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 seeoods (FeV 1.0); peak expiratory flow (PF); maximum mid expiratory flow (IMF); maximum expiratory flow volume curves (MEFV) at 50Z* 25Z and 10Z 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 tha animals' agng process. Zn 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 study from exposurs to respirable PVC dust. Attachments UCC 010746 ------------ --------hjiu.._ i.i ..:.i:i .ii.ig.^i!1.. CKNTRK MM l)IM.A.W> rONIMX. NATIONAL INtninim nx OC llt*AIK>NAL .WKIV ANU lir.Al.lll ft TO Chief, BSft THROUGHt Chief, Pathology Section DATF-: May 5, 1977 D* FROM 1 Veterinary Pathologist, Pathology Section : sukji:ct: Pathology Report on Rata Exposed to PVC Male rats were exposed by inhalation to polyvinyl chloride (PVC), respirable concentration 10 mg/m , for 6 hours/day for S days/week for a period of 12 nonthe. The animals were sacrificed imedlatcly after 12 months of exposure to PVC. The following tissues on each aniaal were saved at necropsy for histopathology evaluation: lungs, liver, heart, spleen, kidney, pancreas, adrenal, thyroid, testis, and urinary bladder. The histopathology evaluation was perfomod on a total of 121 (exposed 57, control 64) male rats. 4 1.1 Rats exposed to PVC 10 e/m* fog 6 hours/day for 5 days/week -"iI by Inhalation. Path. Acca. Ho.; 76-1529, 76-1337, 76-1338, 76-1340 to -1393. Cross pathology: Lungs: Multiple white foci of varying else either in one i or nore lobes of the lungs were seen in 76-1337, -1338, -1344, -1345, -1347, -1348, -1350, -1353, -1354, -1363, -1367, -1369, -1373, -1379, -1385, end -1387. "Abscess" was seen in the lungs of 1 each of 76-1346, -1351, -1352, -1363, and -1378. "Timor" Measuring 1.5 x 2.0 cn and weighing 2.90 ga was seen in 76-1375. Liver: Enlarged dark red liver was seen in 76-1337. Kidney: Small mineralised areas (stones) were seen in the kidneys of 76-1363 and 76-1366. Pituitary gland: Enlarged (ldX) pituitary was seen In 76-1338. His topstholosy: Lungs: The lesions cononly associated with the chronic murine pneumonia (bronchiectasis, peribronchial, and perivascular accimulations of lymphocytes, .focal chronic active bronchitis and bronchiolitis, feral atelectasis) were seen in all rats. Vascular (arterial) wall mineralisation was seen in all rats. Focal intense macrophage accumulations (solid sheets), sometimes displacing the normal structures, were seen. Most of these macrophages hod varying size globular to sphsrical structures in the cytoplasm (foam colls). m *r ucc 010747 J *i I -* > Chief, BSB These dense conglomerations of macrophages were occasionally associated with mild blue staining (mucin?) fluid material. The above-mentioned macrophages or maefophages 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 PVC. No birefringence was seen among these. Or. Stettler and Mr. George Mackay informed me that these, indeed, were PVC particles, based ` on electron probe analysis of some-lungs from the rets exposed to PVC by inhalation as well as by intravenous injection. The macrophage accumu lations apsrt from physical displacement of the lung parenchyma do not seem to bestow any 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 TBLNs examined. Reaetive hyper plasia of germinal centars was also seen. Liver: Mild fatty infiltration of hcpatocytcs 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 were seen in all th spleens examined. Heart: Mild focal myocarditis was seen in 76-1337, -1363, and -1377. Kidney: Multlfoeal mineralized areas of the tubules or the transitional epithelium of the kidney pelvis were seen in 76-1348, -1333, -1336, -1363, and -1366. Focal tubular dilatation, focal tubular epithelial degeneration and regeneration and mild lymphocyte accumulations were sasn in 76-1331, -1356, -1357, -1363, -1370, -1376, -1381, -1382 to -1384, -1387, -1388, -1390 to -1392. Pancreas: Mild hyperplasia of the islets of Langcrhans was aeon In 76-1335, -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 -1330, -1369, -1370. -1378, and -1381. An adrenal cortical adenoma was seen in each of 76-1363 and 76-1371. A phttochromocytoaa was seen In 76-1358. 2 ucc 010748 Chief, BSB 3 Thyroid: Cyst(s) containing keratin wo* seen in 76-1337, -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) well mineralization vas seen in 76-1358, -1378, -1385, and -1390. Mild hyperplasia of interstitial cells and atrophy of seminiferous tubules wore 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. Acca. Mo.: 76-1394 Co -1431, 76-1510 to -1520, 76-1523 to -1537, 76-1539 to -1548, Cross pathology: A cataract of tha right eye was seen in 76-1396. Consolidation of lung lobe* was seen in 76-1395, -1400, -1416, -1527, -1530, -1537, -1540. -1546, and -1547. Brown discoloration (76-1405) and an abscess was seen in- the lungs (76-3418). A multiloculsted mass 2.5 x 3,0 cm was seen attached to mesentery in 76-1427. Renal calculi were seen in 76-1518. Hlatopathology: 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 laaacr degree in intensity wars sean in all rats. Thssa 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 rata. Liver: A single cyst was seen in each of 76-1397 and 76-1399. Spleen: The changes aeon wero 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 cndocrlno elements was seen in 76-1395 to -1399, -1402, -1404 to -1410, -1414 to -1418, -1420, -1421, -1424 to -1426, -1428, -1429, -1510, -1511, -1514, -1515, -1518 to -1523, -1532, -1539 to -3542, and -1545. uco 010749 Oiicf, BSB 4 Kidney: Adrenal: Thyroid: Testis: Eye: Mui: Tubular epithelial degeneration and regeneration, occasional tubular dilate ti n and focal oil Id 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 -1543. Focal mineralisation of tubular epithelium and/or the transitional epltholius of the renal pelvis was aeon in 76-1518, -1527, and -1533. Adenoma of tho adrenal cortex waa notlead in 76-1400, -1518, -1523, and -1544. Fheochromocytoma waa aeon In 76-1548. Moderate fatty Infiltration of tho cortex waa aeon in 76-1410 and 76-1544, Oyst(e) containing keratin waa 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 -1548. Atrophy of seminiferous tubules end Leydlg cell hyperplea la was seen In 76-1395, -1400, -1514, -1516, -3533, -1541, and -1548. Vessel (artery) well calcification was seen in 76-1398 and 76-1533. Focal moderate alncrelixation of seminiferous tibules was seen in 76-1418, -1510, und -1517. 76-1396: Retinal 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 tho hyallnlcation of sclera imparted the opacity to the least cataract seen grossly. 76-1427: Granuloma of mesenteric fat. Comment: For comparison, this comment shall include rat and guinea pig dots. Both the rats and tho guinea pigs exposud to FVC by inhalation exhibited the presence of PVC particulates in tho pulmonary macrophages, although the pattern of macrophage accumulation between the two species differed. There was no inflammatory or any other dclsterious effect scon in* the lungs of these animals chat could be attributable to FVC inhalation. The incidence of portvascular lymphoid aggregations in tho 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 two conditions is not known (Thompson, S. U,t Hunt, R. D. ct al: Am. -I. l*ath. 40:507-517 (1962); Kaufman, A. F.: lab. Anln. Care 20:1002-1003 (1910)) and is worth exploring as N10SN uses guinea pigs as ucc 010750 Chief, BSB 5 one epeciee of animals in bl logical experiments. The nepbrocalcinosis seen in the exposed end control guinea pigs may be related to diet (J. C. Woodard: Am. J. Path, 65:253-268 (1971) and 65:269-278 (1971)). Corollary to tho above observation was the finding ot invariable fatty Infiltration of exocrine and endocrine elements of the pancreas In both the exposed snd control guinea pigs and tho hyperplasia of Islets of Laagerhans seen in both the rats and the guinea pigs employed in this experiment. In additloo, the vascular wall calcification in tha pul monary veasals of rats is disturbing. All of chose "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 cha normal range observed for Sprague-Dawley rsts of this age. / ucc 010751 . MEMORANDUM DEPSKT5!SiTANn ._ CIKTM RM DISFASI! roNTlnl HATMWAt INtTITtm Wl (KCUPAIUtMAI MITtT AVr> |FM III TO ! j Chief, ETB Through: Dircctor, DBBS Chief, BSB OATH: s ptcmber 6, 1978 ^ FROM 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. iI Control male monkeys (10) were maintained in an open aniiaal room 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 (TOLM), mesenteric lymph nodes (MLM), liver, spleen, kidney, urinary bladder, prostate, testis, stomach (pylorus), % duodenum, pancreas, adrenals, and skin from the abdomen were :} saved for histopethology. i 1.1 Control Monkeys Path. AccssT#77"297 5. 77-2979, 77-2981, 77-2983 to 77-2986, 77-2991, 77-2993 and 77-2994. Cross and hlatopathology; See the pathology report on monkeys exposed to Silica-F. j 1.2 Monkeys Exposed to PVC Path. Accss. #77-2974, 77-2976, 77-2980, 77-2982, 77-2988, 77-2989, 77-2995, 77-2996, 77-2997 and 77-2999. Gross Patholoav; 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. Etelargad and black KLNs were seen in 77-2974 and 77-2976. HlatoDatholoay: 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 else in the cytoplasm. About 15Z of the total macrophage aggre gates (macules) in 77-2997, 77-2988 end 77-2980 contained black to brown anisotropic particles of the same dtgrae of dapoaition as in the controls. In the rest of the PVC exposed monkeys 20 to 22Z of I I i * 'jc: ucc 010752 Chief, STB 2 the macules hed theee black to brown particle*. A total of 110 macrophage aggregates were seen at 2SX magnification in most of cho lunge. The diameter of many of these aggregates varied from 100 to 200w while the largest, present in the alveolsr region, measured 475p. The macro phage aggregates were present in the alveolar walls, 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 (P, C snd P) exposed monkeye. Poeal hyperplasia of type II cslla waa present in 77-2989. Smooth muscle hyperplasls was seen around blood vessels and alveolar walla In 77-2996. Acute bronchopneumonia waa seen in 77-2988. Plant material waa praaant in a bronchua in 77-2999. Multiple gaint calls away from the plant mnterlal were seen in the 77-2999. Mon-inflammatory arterlopathy aa In the controls waa present in all these monkeys. TBLM: As in the controls the medulla contained macrophages with snlsotropie particles. In addition, other macro phages with cytoplasmic material (PVC - blue in color - see lung) were present. Together, these macrophages replaced moat of the medulla of the TBLMe la all monkeys. Liveri Diffuse fatty infiltration of tho hepatocytas was present in 77-2982 and 77-2996. Kidney: Multifocal calcification of cortical tubules was seen in 77-2993. MLH: See the controls. The other tissues examined were unremarkable. Comment: A slightly higher number of macrophage aggregates containing . black and brown blrafrlngent particles were seen in PVC exposed than in cite control monkeys. The pattern of distribution of the macrophage accumulations in the PVC sxposed snd the amorphous silica (P, C and P) exposed monkey lungs snd the TBLNs was similar. The macules were smaller In also in PVC exposed than thoso seen in the amorphous silica (F, C and P) exposed monkeys. The monkey lung reaction suggests that It may be a ucc 010753 Chief, TB 3 non-specific one, inasmuch as these materials (PVC and amorphous silicas-F, C and P) show diverse chemical composition. Tho second paragraph under "Comment" in the pathology report on monkeys ex posed to amorphous sillca-F 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-contalnlng macrophages. Choudarl Kommlneni, Ph.D., DVM uoc 010754 .memorandum DEPAKTMKNT OH III AtTM. liDUCATlON. AND WR-HAUI: YUM 10 HUAI III Nl kVH'l- Cr.Nll R HIM IMF AMI ( ON I Ml* national iNnmnK nm nr htaiminai. .\am--iv ani> iiiamii iTO : Chief, BSB 111R0UCH: Chief, Pathology Section OATU: May 10, 1977 *fROM : Veterinary Pathologist, Pathology Section iUBJECT; Pathology Report on Guinea Plga to PVC Male guinea pigs vere exposed byainh*lation to polyvinyl chloride <PVC), respirable concentration 10 mg/m , for 6 hours/day for 5 days/week for a period of 12 months. The animals were sacrificed lmmudlately after 12 months of - exposure to PVC, The following tissues on each animal were saved at necropsy for hlstopathology evaluation: lungs, liver, heart, spleen, kidney, pancreas, adrenal, thyroid, testis, and urinary bladder. The hlstopathology evaluation was performed on a total of 75 (exposed 36; control 39) male guinea pigs. 2.1 Guinea piss exposed to PVC 10 mg/m* for 6 hours/day for 3 days/ week by Inhalation. Path. Acca. Mo.i 76-1432 to 76-1467. Cross 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, end -1449. Small areas of necrosis In the liver of 76-1443 were seen. Mesenteric fat necrosis was found In 76-1438 and 76-1441. Histopatholoav: Lungs: All guinea pigs exhibited moderate amount of eosinophilic serous exudata mixad with mild to moderate numbers of splthelisl cells (decidual showing varying stages of de generation) in the bronchial lumens. Another common find ing among all guinea pigs was the presence of multiple *88togstea of lymphocytes. Most of theso lymphoid aggregates vara oriented around or near small arteries or veins, thus giving an appearance of lymphoid follicles. The interstltium of all the lungn ulwvod numerous macrophages. These macrophages contained spherical to globular hollow structures In the cytoplasm. These macrophages did not Sgregetc in the seme fashion as tliosc 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 la 76-1434, -1435, -1438, -1446, -1452, -1453, -1455, and -1456. Focal atelectasis was' seen in the lungs of all guinea plga examined. ucc 010755 Chief, BSB 2 Liver: Mild fatty infiltration of hepat cycee wee seen in 76-1432, -1441, end -1467. The histology slides from 76-1443 did not show any hepatic necrosis* Search f r liver tissue with necrotic areas from "wet tissue" was not fruitful. Heart: Focal alld 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 alld mineralization of tubular epithelium . was 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, -14S3, and -1462 to -1465. 2.2 Untreated guinea pigs Path. Acca. Ho.: 76-1470 to 76-1508. 1 Cross pathology: Consolidation of lungs was seen la 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* Hecrotlc fat (mass) was found attached to mesentery of 76-1475 (3.57 gn), -1477 (3 x 2 cm), -1480 (4.5 x 2.5 cm), -1486 (1.0 x 2.0 cm), -1494 (1x2 cm), -1495, and -1496. Hlstopathology: 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 interstitium of all the lungs contained lesser number of macrophages than thoso seen in 2.1. The cytoplasm of these macrophages was granular and eosinophilic. Plant material with or without r Inflammatory infiltrates was seen In 76-1488 and -1490. Bone formation In tlie alveolar region was seen in -1474, -1475, -1476, -1478, -1490. -1493, -1499, -1501, and -1506. Focal consolidation of all lungs was seen. t ucc 010756 Chief, BSB 3 Liver: Fatty infiltration (mild) of hcpat cytes was seen In 76-1472 and 76-1478. Moderate hyperplasia of bile ducta wee seen in 76-1474. A nycl llposercome was seen in the liver of 76-1470. Spleen: Macrophages with yellow granular Material in the cyto- pleea were seen in all guinea pigs. Kidney: Multifocal nild to Moderate Mineralization of tubular epithelium was seen in 76-1470, -1471, -1473 to -1483, -1487 to -1508. Peneresa: Fatty infiltration of exocrine and endocrine elements wee seen in 76-1470 to -1475, -1478, -1480, -1482, -1486, -1488, -1490, -1492, -1494, -1495 to -1497, -1501, -1502, -1503, and -1507* The pancreas from the remaining guinea pigs showed fatty infiltration of exocrine elements end 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 wee 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: Cranuloma of mesanterlc fat; polarising yellow material seen. 76-1494: Degenerating fat. 76-1496: Granuloma of mesenteric fat. Cojment: For comparison, this comment shell include ret and guinea pig data. Both the rets and the guinea pigs exposed to PVC by Inhalation exhibited the prosenee of PVC particulates iu the pulmonary macrophages, elthough the pattern of macrophage accumulation between the two species differad. There was no lnflanetory or any other doleterlous effect seen in the lungs of these animals that could be attributable to PVC inhalation. The Incidence of perivascular lymphoid aggregations in the lungs of gulnc pigs was similar in both exposed end controls. The presence of bony spi cules in the lungs of exposed end control guinea pigs was observed. The pathogenesis of these two conditions is not known (Thompson, S. W., Hunt, R. D. et al: Am. J. Path. 40:507-517 (1962); Kaufman, A. F.: Lab. Aniia. Care 20:1002-1003 (1970)) and is worth exploring ns N10SH uses guinea pips as one species of animals in biological experiments* The ncphrocalclnosis seen in the exposed and control guinea pigs may ba related to diet (J* C. Woodard: Am. J, Path. 65:253-268 (1971) end 65:269-278 (1971)). Corollary ucc 010757 Chief, USB 4 to the above observation was the finding of Invariable fatty Infiltration of exocrine and endocrine elements of the pancreas in both the exposed and control guinea pigs and cite hyperplasia of Islets f Langcrhnns seen In b tti the rats and the guinea pigs employed in this experiment. In addition, the vascular wall calcification in the pulmonary vessels of rats is disturbing. All of these "incidental" findings strongly suggest that those animals had metabolic problems probably related to the animal diet. The changes seen in cite 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-Dawley rats of this sge. Cho_ .Mi ucc 010758 PLA^iCS DIVISICR NOTE ON A TELEPHONE CONVERSATION WITH OK H N JOWSON OF BF GOODRICH, 20 OCTOBER 1978 PVC DUST - NTOSH STUDIES Dr Johnson 'phonod to soy ho hod now had a talk with Dr Trent Lewis of NIOSH on the 3 eaeeal study. Or Lewis emphasised that this was in n sense a carcinogenicity study. It was a study aimed at ascertaining about pulmonary function end fibrosis* Dr Lewis was happy with th utcome of the work in that nothing happened and there was nothing to comment on the subject ot pulmonary function and fibrosis. He thought the study was totally unsuitsd to gauge earcinogenecity. In Dr Lewis's view an inhalation study of PVC dust on animals to demonttrat carcinogenicity is a very'difficult undertaking. He would be very unwilling to tackle it unless there was something equivocal in the epidemiology tiiat needed to bo 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 make any difference and again he stressed that dust inhalation tests f r carcinogenicity on animals are long, tedious, difficult and uncertain.* J Stafford Division Manager Health & Environment Protection JS/MJE/DSO-107 23 October 1978 Circulation Dr W G F Adams Dr D P Duffield Dr G Pigott Dr 8 W Duck Dr M Sharrott Dr P Grosso Dr J T Carter Dr D W Plester Dr G Paddle Dr K S Williamson Dr I F H Purchase Sir C Lawrence*Jones Dr F W 8est Mr G J Sleddon Mr W Adams Mr R Hards Mr P H M Shorr ck Mr T L Phillips Mr B N P Hutchesson Mr H M Clayton Mr T W Hoffitt Dr L de Boer Dr J G Kammuller Mr J C Thomas Mr M Bonnefoy 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 Whit , Duperial SAIC Chi f Medical Officer, AECI ucc 010759 po Bov ,N0 *tCsivtu srr mperiai City Harttordsftre AL71HD qCT 2 7 19IB LirtniJ Chemical letooham- Welwyn Garden 23400 (STD Cods 07073) Tate* 264291 W N. WHERtfl. ^Xn^ Industries Lxnited From J Stafford Mvlntaa Manager Bae7tflECBMflftd--eut Protection To 0EC 0 7 1978 See Cireulitioa Below ^ WHEELER, JR. TO: Pfastics Division SPI VINYL SUBCOMMITTEE FROM: W D QavWR N Wheeler November 28, 1978 Your ret. PVC DOST Our ref JS/AMB/DSO-107 Tel eel 3162 Oete 17 October 1978 Toa lay ear* to a** the attached letter and NIOSB report X have received froo Dr Douglas of BUS. Thia report aeeos reassuring bet 1 would welcome' the opisioa of our Medical Conlttee who have been considering bow to design a good PVC duat inhalation study. Baa the need for each a study disappeared aa a result of the KZ08H work? Or M N Johnson of B F Goodrich, when he saw us on 9 October, knew of these results but was critical that the rodent species were sacrificed at 12 noatha (nonkeys 22 noatha). Dr Johnson thought that a well conducted full life study on PVC duat in halation should still be considered and the possibility of Transatlantic cooperation explored to derive both protocol and funding. Circulation Dr V G F Adana Dr D P Duffield Dr G Figott Dr B V Dusk Dr M Sharratt Dr P Grasse Dr J T Carter Dr D V Plaster Or G Paddle Dr X S Willi ancon Dr I F X Purchase Sir C Lawrence Jones Dr F V Best Mr G J Sleddea Mr W Adans Mr B Bards Mr P B M Sharroek Mr T L Phillips Mr B N P Butchanson Mr H M Clayton Mr T V Moffltt Dr L do Boer Or J 0 Kannuller Mr J C Thonas Mr M Bonaefoy Dr T Garlands Dr M N Johnson Dr T B Torkelson Wtr-B X.Whsaler (Jr)* JS (2) Dr B I Davies. XCI Melbourne Mr X B White, Duperial SAXC Chief Medical Officer, AXCZ No ?1|019 0**<t i*iq**i Chr*<4 Howtt. Maibpnk. lodoft$WlP ucc 010760 i V* i iis! 'i xuai Health & Safety Executive Barnards House 1 Chepstow Place London W2 4TF TaMphone 01-239 34M aw Dr J Stafford Division Manager Health A Environment Protection ICI Limited, Plastics Division P 0 Box Ho 6 Bessemer Road Welwyn Garden City AL7 1HD Your rafatanca Our rafaranca 1/MS/406/225/73 Odt* 6 October 1978 Dear Dr Jftaf:frd FVC DUST Thank you for sanding ae a copy of tfcxweiler's rep rt on FVC dust and the item froa 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. I enclose copies of the reports given to ae by Dr Harris* Yours sincerely D B Douglas Deputy Director of Medical Services cc: Dr R Owen Dr F:S Fairweather UCC 010761 PVC Chr nic Inhal tion Toxic logy Study Polyvinyl chloride (PVC) la widely uaed la various form*. Rigid PVC la used for cubing and fittings (insulation material and drainage pipe), foils, fllas and sheeting (packaging, recording tapes), profiles (blinds, window frames), tiles, sound records, and fibers. Flexible PVC la used for cables, foils (decoration, roof covering), tubing, artificial leather, flooring, foam rubber, paint, varnish (lacquer), end toys. .. Reports- of pulmonary dysfunction and pneumoconiosis la 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 polymerisa 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. P. Goodrich Company Is a supplier of resins for vinyl dispersions using the trade name "Geon." The dispersions are fluid suspensions of special fine particle-alse polyvinyl chloride resins in plasticising liquids. When the system Is heated to about 148 to 177*C (300 to 3S0*V), fusion (mutual solubilisation of resin and plasticiser) 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 "plastlsol" is used to describe a vinyl dispersion which contains no volatile thlnners or diluents. Plastlsols often contain stabilisers, fillers, and pigments along with the essentials, dispersion resin and liquid plasticiser, but all ingredients have very low volatility under the processing and use conditions. Geon 121 is a high molecular weight resin. It has been the standard of the plastlsol industry for over 23 years and is an excellent resin for starting point formulations. Currently, it is being used la dip, slush and rotational molding, spread coating, foam coating and molding, crown and jar aaals, and caulks and sealants* In light of the relationship unequivocally establlahed 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 (PVC) dusts manufactured and used from polymerisation of the vinyl chloride monomer, DBBS in FT*75 In its project plan on "Chronic Exploratory Toxicology Studios and Test of Validity of Industrial Air Standards" proposed an inhalation exposure study with PVC dust. Actual exposures to e representative material (B. P. Goodrich Company, Geon 121) began in February 1978 utilising three species of animals -- monkey, guinea pig and rat*-- a 6-6-1/2 hours per day, 3 days per week exposure regimen, and at a 10 mg/m* respirable PVC dust concentration. Exposure duration was for 22 months. TIm following table summarises the above data. 4 ucc * 010762 Selected Date froa PVC Chronic Inhalation Exposure Study (Ceon 121) Aalcal Species Monkey Guinea Pig Rat No. per Group Exposed Control 10 10 40 40 00 so Duration of Exposure Calendar Exposure Exposure Davs Days Hrs. Mean PVC Cone. /* . 690 464 2018 10.8 379 245 1428 10.6 376 244 1424 * 10.6 Mean Range of Cone. mg/n* 4.65-9.25 * - ' CT Values (g/*-Hrs.) * Intended Actual 28,180 14,700 14,640 30,510 14,698 ,V" 14,627 ucc 010763 r9 Particle else analysis of collected exposure chamber samples Indicated that the generated PVC dust was of a geometric mean diameter of 0.53um wfth more than 99Z of the sampled particles below 5.0um; 82Z below 1.0pm. The manufacturer's specifications data states a particle size range for Ceon 121 of between 0.S and i.Swa. Exposure Systemt 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" H*0. The PVC aerosol was generated by means of a Vrlght Dust Feed Mechanism 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). Bioloaical response data evaluated from the exposed and control animals at time of serial sacrifice/evaluation Included: Blochsmlcal/Clinlcal Chemistry (Guinea Pig, Rat only): (SCOT, SGFT, alkaline phosphatase, gamma glutamyl transpeptidase, total protein and serum-protein electrophoresis). Ho significant differences were Indi cated In rats for any parameter. Guinea pig data showed controls with higher SCOT, SCPT, 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 bef re 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 dqat deposition and retention to pulmonary tissue morphology was aggregation bf PVC-contalnlng 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 (TIC); 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 volme in 1.0 seconds (FeV 1.0); peak expiratory flow (FF); maximum mid expiratory flow (IMF); maximum expiratory flow volume curves (MEFV) at 502, 25Z and 10X 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 tho animals' aging process. In most cases dlffhrences were noted during the -sane second and third testing periods (exposure months 6 and 14) and were indi cative of soma small airway obstruction. At this time, however, these differences were not statistically significant. At the last evaluation (month 22) compared with baseline (pro-exposura) data there ware no signi ficant differences for any parameter tested. Impairment of respiratory function does not appear to be Indicated under the conditions of this study from exposure to respirable PVC dust. Attachments d ucc 010764 iVi. i^jviOivrxi Si-nzrxVT CUNTF.H I OH HIM. ASF CONI Hoi NATIONAL. INST ITTITU FIW tK( Ol'AIKINAL NAIIil V ANII IITAI lit TO : Chief, USB THROUGU: Chief, Pathology Section DATE: May 5, 1977 FROM Veterinary Pathologist, Pathology Section SUHJIiCT; Pathology Repox t on Ref Exposed to PVC Male rats were exposed by inhalation to polyvinyl chloride (PVC), respirable concentration 10 mg/m , for 6 hours/day for S days/wcok for a period of 12 months. The animals were sacrificed immediately after 12 months of exposure to PVC. The following tissues on each animal vers saved at necropsy for histopathology evaluation: lungs, liver, heart, spleen, kidney, pancreas, adrenal, thyroid, testis, end urinary bladder. The histopathology evaluation was performed on e total of 121 (exposed 57, control 64) male rats. 1.1 Rats exposed to PVC 10 me/m* for 6 hours/day for 5 davs/wack by Inhalation. Path. Accs. Wo.: 76-1329, 76-1337, 76-1338, 76-1340 to -1393. Cross pntholor.y: Lungs: Multiple white foci of varying else 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, end -1387. "Abscess" wee seen in the lungs of each of 76-1346, -1351, -1352, -1363, sad -1378. "Tumor" measuring 1.5 x 2.0 cm end weighing 2.90 gm - was seen in 76-1375. Liver: Enlarged dark red liver wee seen in 76-1337. Kidney: Snell mineralized areas (stones) wers seen in the kidneys of 76-1363 end 76-1366. Pituitary gland: Enlarged (10X) pituitary wee seen In 76-1338. Hietonetholoev: Lungs: The lesions eoanonly associated with the chronic - murine pneumonia (bronchiectasis, peribronchial, and perivascular acctaulaclons of lymphocytes, .Coca) chronic active bronchitis end bronchiolitis, focal atelectasis) were seen in all rats. Vascular (arterial) well mineralization was seen .in nil rate. Focal intense macrophage accumulations (solid sheets), sometime displacing tho normal structures, were scon. Most of thene macrophages had varying size globular to spherical structures in tho cytoplasm (foam calls). UCC 010765 K Ui Chief, BSB These dense conglomerations f 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 PVC. No birefringence was seen among these. Dr. Stettler and Mr. George Mackay informed . me chat these, indeed, were PVC particles, based ( 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 seen to bestow any dele terious effects on these rats. No slteratlons (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 sesn in the medulla and cortex of all the TBLNs 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 were seen in all th spleens examined. Heart: Mild focal myocarditis was saan 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 hyporplasia of the islets of Langorhans 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 tho cortex was seen in 76-1341 to -1344, -1348 to -1350, -1369, -1370, -1378, end -1381. An adrenal cortical adenoma was seen in each of 76-1365 and 76-1371. A pheochromocytoms was seen in 76-1358. ucc 010766 Chief, USB 3 Thyroid: Cyst(s) containing keratin was seen In 76-1337, -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 Mineralization 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' Rata Path. Acca. Mo.: 76-1394 to -1431, 76-1510 to -1520, 76-1523 to -1537,.76-1539 to -1548. Cross pathology: A cataract of ths right eye was seen in 76-1396. Consolidation of lung lobes was seen in 76-1395, -1400, -1416, -1527, -1530, -1537, -1540, -1546, and -1547. Brown discoloration (76-1405) and an abscesa was sesn in- tho lungs (76-1418). A multiloculated mass 2.5 x 3.0 cm was seen attached to mesentery In 7fr-l427. Renal calculi were seen in 76-1518. Histopstholonr: Lungs: The morphological changes associated with the chronic murine pneumonia and pulmonary vascular wall minerali zation as seen In 1.1 wars sesn 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 waa saen in any rat. TBLN: Chronic reactive hyperplasia was a common finding in all rats. Liver: A aingle 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 endocrino olemontn was seen in 76-1395 to -1399, -1402, -1404 to -1410, -1414 to -1418, -1420, -1421, -1424 to -1426, -1428, -1429, -1510, -1511, -1514, -1515, -1518 to -1523, -1532, -1539 to -1542, and -1545. ucc 010767 <2>icf, BSB 4 Kidney: Adrenal: Thyroid: Testis: Eye: Bui: Tubular epithelial degeneration and regeneration, occasional tubular dilatatl n and f cal olid 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. Focal mineralization of tubular epithelium nud/or the transitional epithelium of the renal pelvis was seen in 76-1518, -1527, and -1533. Adenoma of the adrenal cortex was noticed in 76-1400, -1518, -1523, end -1544. Phcochromocytoma was seen In 76-1548. Moderate fecty infiltration of the cortex was seen in 76-1410 and 76-1544. 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 -1334, -1536, -1541, -1543 to -1548. Atrophy of seminiferous tubules and Leydlg cell hyper plasia wee 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 mineralization of itcminiferou* cibulcs was seen in 76-1418, -1510, and -1517. 76-1396: Retinal atrophy - .unilateral* Adhesions between the retina and lens with dystrophic calcifi cation at soma foci. The lens protein was well oriented with occasional basophilic bodies, probably nuclei from decidual lens cells. The calcific deposits coupled with ths hyallnisation of sclera imparted the opacity to the leas; cataraet seen grossly. 76-1427: Granuloma of mesenteric fat. Comment: For comparison, this comment shall Include rat and guinea pig data. Both the rats and tha guinea pigs exposed to FVC by Inhalation exhibited the presence of PVC particulates in the pulmonary macrophages, . although the pattern of macrophage accumulation between the two species differed. Titers was no inflammatory or any ocher deleterious effect seen in'the lungs of.Chess animals that could be attributable to FVC Inhalation. The Incidence of porlvaacdlar lymplinid aggregations In ths 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 obsurved. The patho genesis of these two conditions is not known (Thompson, S. W., Hunt, R. D. ct el; Am. J. l'afh. 40:507-317 (1962); Kaufman, A. P.: hob. Anim. Care 20:1002-1003 (1970)) end is worth exploring as N10SH uses guinea pigs as , *p a.* ucc 010768 Chief, BSB 5 one species of animals in blol gical experiments. The ncphrocalcinosis seen is the exposed end control guinea pigs may he related to diet (J. C. Woodard: Am. J. Path. 65:253-268 (1971) and 65:269-278 (1971)). Corollary to tho above observation was the finding of invariable fatty infiltration of exocrine and endocrine elements of the pancreas in both the exposed and control guinea pigs and tho hyperplasia of islets of Langerhans seeo in both the rats and the guinea pigs employed in tills 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 Sprsgus-Dawley rats of this age. UCC 010769 MEMORANDUM to : Chief, ETB Through! nifai-inr. nM< UfcT'AK iwtNl' OF HEALTH. KLHJOA HON, AND WEI TAKl PUBLIC HEALTH SERVICE CCMTEK POt DISKA5K CONTMfH. NATIONAL INSTITUT* POE OCCUr4 1 MINAl iUITTV AST* Hr AM II DATE: September 6, 1978 i ^ from i| SUBJECT: Research Veterinary Medical Officer Pathology Report on Monkeys Exposed to PVC Ten male Cynooolgus monkeys were exposed Co 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 anlmtl rood In their Individual cages. The nonkeys were killed within 48 hours after the final exposure. At the tlae of autopsy, tissues fro the lungs (sll lobes with trschea), thyroid, heart, tracheobronchial lymph nodea (TBLM), nesenterlc lymph nodes (MLN), liver, spleen, kidney, urinary bladdar, prostate, testis, stonsch (pylorus). l duodenum, pancreas, adrenals, and akin from the abdomen were ;-l saved for hlstopathology. 1.1 Control Honksys Psth. Accss. #77-2975. 77-2979, 77-2981, 77-2983 to 77-2986, 77-2991, 77-2993 and 77-2994. Cross and hlstopsthology: See the pathology report on Monkeys exposed to Silica-F. '* 1.2 Monkeys Exposed to PVC Psth. Accss. #77-2974, 77-2976, 77-2980, 77-2982, 77-2988, 77-2989, 77-2995, 77-2996, 77-2997 and 77-2999. Cross Pstholosvt Adhesions between the lobes of the lung end the cRoraclc wall were seen In 77-2980, 77-2995 and 77-2997. Multiple black areas were seen In the lunge of 77-2976, 77-2980, 77-2982, 77-2988, 77-2989, 77-2996, 77-2997 end 77-2999. En larged and black MLHs were seen In 77-2974 and 77-2976. Hletopatholosyi Lungt Macrophages with anisotropic particles as In the controls wars similarly present in all these nonkeys. Adntxsd with these Macrophages wars other Macrophages with spherical Material (PVC) of varying else in the cycoplps*. About 15Z of the total nocrophago 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. lm the rest of the PVC sxposSd monkeys 20 to 22Z of ucc 010770 Chief, ETh 2 the oeculea had theae 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 200v while the largest, present In the alveolar region, measured 475ii. The macro phage aggregates were present in the alveolar walls, 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. Vlth 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 F) exposed monkeys. Focal hyperplasia of type XI cells was present in 77-2989. Smooth muscle hyperplasia was seen around blood vessels and alveolar walls In 77-2996. Acuta bronchopneumonia was seen in 77-2988. Plant material was present in a bronchus in 77-2999. Multiple gaint cells away from the plant material were seen in the 77-2999. Non-inflamnatory arterl pathy 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 mscrophages replaced most of the medulla of the TBLNs in all monkeys. Livers Diffuse fatty infiltration of the hepatocytcs was prasent In 77-2982 and 77-2996. Kidney: Multifocal calcification of cortical tubules was seen in 77-2995. MLHs Sae the controls. The ocher 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, C and P) exposed monkey lungs and the TBLNs was similar. The maeulcs were smaller in slie 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 ucc 010771 Chief, STB 3 non-specific one, inasmuch as these materials (PVC and amorphous silicas-F, C and P) show diverse chemical composition. The second paragraph under "Comment" in the pathology report on monkeys ex posed to amorphous slllca-F 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-contalning macrophages. Choudari Komminenl, Ph.D., DVM ucc 010772 , MEMORANDUM ` DEPAKTMriNT OV 111 ALTlf, HDUCAT10N. AND WI-U'AIU- HUH IC IIHAI lit M KVK I- CrKlI C HIM tUMIMIH NATIONAL INfllTltlM I*H lift IlfAIHIMAI. .NAKI-1Y ANII III A< 111 TO Chief, BSB THROUGH: Chief, Pathology Section DATI-: Hay 10, 1977 X irnOM Veterinary Pathologist, Pathology Section Pathology Report on Guinea Plga to PVC Male guinea plga were exposed by^inhalatlon to polyvinyl chloride (PVC), respirable concentration 10 ng/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 ver saved at necropsy for hlstopathology evaluation: lungs, liver, heart, . spleen, kidney, pancreas, adrenal, thyroid, testis, and urinary bladder. The hlstopathology evaluation was performed on a total of 75 (exposed 36; control 39) msle gulnes pigs. 2.1 Guinea piss exposed to PVC 10 mg/m* for 6 houra/day for 3 days/ week by inhalation. Path. Acca. Ho.: 76-1432 to 76-1467. Cross pathology: Yellow specks were seen in the lungs of 76-1434, -1436, -1459, and -1464. Consol IdatIon of lungs was observed In 76-J435, -1437, -1439, and -1449. Small areas of necrosis in the liver of 76-1443 were seen. Mesenteric fat necrosis was found in 76-1438 and 76-1441. I Hlstopatholoav: TIt 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 lumens. Another common find ing among all guinea pigs was the pretence of multiple aggregates of lymphocytes. MoaL of these lymphoid aggre gates wars oriented around or near small arteries or veins, thus giving an appearance of lymphoid follicles. The lnterstltium of all the lungs showed numerous macrophages. These macrophages contained spherical to globular hollow structures In tha cytoplasm. Thess macrophages did not aggregate in the same fashion as tliosc seen in rat lungs (1.1). Plant material with or without associated Inflam mation was seen In bronchioles of 76-1432 and 76-1433. Bone formation (small splculus) In alveolar area was seen la 76-1434, -1435, -1438, -1446, -1452. -1453, -1455. and -1456. Focal atelectasis waa' soon in the lunga of all guinea pigs examined. Chief, BSB 2 Liver: Mild fatty lnfllcracl n of hepac cytes was seen In 76-1432, -1441, and -1467. The histiology slides from 76-1443 did not show any hepatic necrosis. Search for liver tissue with necrotic areas from "wot tissue" was not fruitful. Heart: Focal nild 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 mineralisation of tubular epithelium . was 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 nild mineralisation 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 guinea pies Path. Acce. Ho.: 76-1470 to 76-1508. i Cross pathology: Consolidation of lungs was seen in 76-1488, -1490, -1506. Small necrotic foci were seen in the livers of 76-1486, -1488, 1 and -1491. A contracted kidney was seen in 76-1493. Necrotic fat (mss) wsa found attached to Mscntery of 76-1475 (3.57 gm), -1477 (3x2 cm), -1480 (4.5 x 2.5 cm), -1486 (1.0 x 2.0 cm), -1494 (1x2 cm), -1495, and -1496. Hlatopathology: Lungs: The presence of eosinophilic fluid exudate with cellular T debris and the lymphoid aggregation in all guinea pigs was the same as seen in 2.1. The interstltium of all the lungs contained lesser number of macrophages than those seen la 2.1. The cytoplasm of these macrophages was granular and eosinophilic. Plant material with or without inflammatory infiltrates was assn In 76-1488 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 soon. : i- UCC 010774 Chief, BSB 3 Liver: Tatty infiltration (aild) of hepatocytcs wee seen in 76-1472 end 76-1478. Moderate hyperplasia of bile ducts was seen in 76-1474. A nyclollposarcoma was seen In the liver of 76-1470. Spleen: Macrophages with yell v granular material in the cyto plasm were ssen in all guinea pigs. Kidney: Multifocal mild to moderate mineralization of tubular epithelium was seen in 76-1470, -1471, -1473 to -1483, -1487 to -1308. Pancreas: Tatty infiltration of exocrine and endocrine elements was seen in 76-1470 to -1473, -1478, -1480, -1482, -1486, -1488, -1490, -1492, -1494; -1495 to -1497, -1501, -1302, -1303, and -1507. The pancreas from the remaining guinea pigs shewed 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, -1473, -1480, -1493, -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: Cranuloma 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 yellow material seen. 76-1494: Degenerating fat. 76-1496: Cranuloma of mesenteric fat. Comment: Tor comparison, this comment shell Include rat and guinea pig data. Both thd rets and the guinea pigs expised to PTC 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 daleterioua effect seen In the lungs of these animals that could be attributable to PVC lnhalati n. The incidence of perivascular lymphoid aggregations in the lungs of guinea pigs was similar in both axposed end controls. The presence of bony spi cules in the lungs of exposed end control guinea pigs was observed. Th pathogenesis of these two conditions is not known (Thompson, S. W., Hunt, R. D. et al: Am. J Path. 40:507-517 (1962); Kaufman, A. F.: Lab. An!a. Care 20:1002-1003 (1970)) and is worth exploring ns N10SH uses guinea pigs as one~specles of animals in biological experiments. The nephrocalclnosls seen in the exposed and control guinea pigs may be related to diet (J. C. Woodard* Am. J, Path. 5:253-268 (1971) and 65:269-278 (1971)). Corollary j. i - ~ 7 ^~* n`i "'fCnf a ~'r w - v* `W ucc 010775 Chief, BSB 4 t the above obscrvatl n was the finding f Invariable fatty Infiltration of exocrine and endocrine elements f cite pancreas in both the exposed and control guinea pigs and the hyperplasia f islets f Langcrlmns seen In both the rats and the guinea pigs cmpl yed in this experiment. In addition, the vascular wall calcification In the pulmonary vessels f rats is disturbing. All of those 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-Davley rats of this aga. *y 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 ho hod now had a talk with Dr Tront Lewis of NIOSH on the 3 mammal study. Dr Lewis emphasised that this wos in n sense a carcinogenicity study. It was a study aimed at ascertaining about pulmonary function and fibrosis. Dr Lewis was happy with the uteom of the work in that nothing happened and there was nothing to comment n the subject ot pulmonary function and fibrosis. He thought the study was totally unsuited to gauge carcinogenecity. In Dr Lewis's view an inhalation study of PW dust on animals to demonstrat carcinogenicity is a very'difficult undertaking. He would be very unwilling to tackle it unless there was something equivocal in the epidemiology tliat needed to be resolved. Even then he would advocat expanding the epidemiology to get a more positive answer. If there is a positive answer from the epidemiology no amount of animal work would mak any difference and again he stressed that dust inhalation tests f r carcinogenicity on animals ere long, tedious, difficult and uncertain.' J Stafford Division Manager Health & Environment Protection JS/MJE/DSO-107 23 October 1978 .. Circulation Dr W G F Adams Dr D P Duffield Dr G Pigott Dr B W Duck Dr H Sharratt Dr P Grosso' Dr I F H Purchase Sir C Lowrence-Jones Dr F W Best Mr G J Sleddon Mr W Adams Mr R Hards Mr P H M Sharr ck Mr T L Phillips Mr B N P Hutchesson Mr H N Clayton Mr T W Moffltt Dr L do Boer Dr J G Kdmmuller Mr J C Thames' Mr M Bonnefoy Dr T R Torkelson Mr R N Wheeler (Jr) JS (2) Dr R E Davies, ICI Australia Mr K H White, Ouporial SAIC Chief Medical Officer, AECI ucc 010777