Document e79w594wg7nvZxM06nJydrg1M

I r r- X ?* f' r i; THE PROBLEM OF POSSIBLE SYSTEMIC EFFECTS FROM CERTAIN CHLORINATED HYDROCARBONS* Cecil K. Drinker, Madeleine Field Warrenand Granville A. . Bennett - . . -. Department of Physiology, Harvard School of Public Health and Department of Pathology, t - Harvard Medical School, Boston, Mass. ... : ._ HE use of chlorinated naphtha lenes and compounds of allied pharmacological possibilities is extremely vide, and with the steady growth of the use of electricity is cer tain to expand much farther. For years it has been known that many of these compounds cause a troublesome acne, and there is a large literature upon this phase of the subject. Our investigations have not been concerned with chloracne but with the possibility of systemic effects following ingestion or inhalation of such products. In the spring of 1936, the Halowax Corpora tion, a division of the Bakelite Cor poration, called our attention to three fatal cases of jaundice in workmen using chlorinated naphthalenes and chlorinated diphenyl, and requested that the subject be investigated as * Received (or publication June 30, 1937. rapidly and thoroughly as possible.t In brief these cases were as follows: Patient 1. Male, age 21. The previoua: medical history of this man was in no way~ significant except for the fact that he had an attack of jaundice about 6 weeks prior to his fatal illness. Late in December, 1936, he became badly constipated and had much abdominal pain and distention. When ad mitted to the hospital he was slightly jaun diced and was evidently very ill. He was somewhat anemic and his skin, particularly upon the arms/face, chest and back, showed many pustules. He died after a brief period in the hospital, and at autopsy was found to t The Halowax Company makes many products besides chlorinated naphthalenes, and it has come to our knowledge that all of these products are. indiscriminately called "halowaxes" by purchasers and users, and are lumjied together as possible causers of acne and even of systemic disease. Since "halowax" is merely a trade designation, care should be taken to describe compounds by their chemical^ names and thus avoid condemnations which are both troublesome and misleading. ........ r v-. DSW 346088 STLCOPCB4084407 --J^.v.^.:-..nf V-' 1%^.C--.-,- j-<. 284 JOURNAL OF INDUSTRIAL IIYGIENE AND TOXICOLOGY [Sept. 19S7 have a cirrhosis of the liver with acute yel low atrophy superimposed upon it. This man had been exposed to low concentrations of vapors arising from a mixture of tetra and pentachlornaphthalcnes, together with approximately 10 per cent of a refined chlorinated diphenyl. W hile both he and others engaged in the same work had chloracne, there were no other disturbances of health in fellow workmen, nor was there any pre cipitating cause for the acute yellow atro phy such as treatment with arsphenamine or exposure to dangerous coucentrations of carbon tetrachloride. Patient . This was a young man who died in February, 1936, after an acute illness characterized by jaundice. He had been exposed to fumes arising from a mixture of pent*. and hexachlornaphthalenes. There is no record of chloracne. The patient worked with a large number of other people of whom but one (Patient 3), a close friend, had significant illness. Patients. Another young man employed with Patient 2. He became jaundiced in March, 1936, and died after an illness of 2 weeks. A careful autopsy resulted in a diagnosis of acute yc*lo atrophy of the liver Here again no history could be ob tained cs to a precipitating cause, and there was nc record of preceding attacks of jaundice. In addition to these three very re cent fatalities, we have learned of four other possible cases, none of them fatal. All of these have had jaundice and the entire group consists of iso lated individuals who have been picked out of large groups having the same exposure. In but one instance. Pa tient 1, is there record of antecedent disturbance of health, and the general health of fellow workers has been good. Such cases have not been reported in the medical literature and only occa sionally can one find reference to sys temic effects of any sort. For exam ple, Courtois-Suffit (1934) reports on work done by Touraine and his asso ciates (1934) who examined GO workers who had been exposed to trichlor- naphthalene. Of these 13 were found to have mild digestive complaints, anorexia, nausea and vertigo, but Courtois-Suffit remarks finalty, "Absorption is certainly possible and we have for proof of it some of the diges tive and general complaints which have been due to it. But they appear to be of little consequence considering the mildness of the digestive troubles and the absence of respiratory phe nomena.1' ... In Touraine's cases the exposure was to a t-riclilomaphthalcne, whereas the American cases of acute yellow atrophy were exposed to compounds of higher chlorination. Our own experiments indicate that triehlornaphthalcnes re quire enormous dosage, far beyond anything encountered in industry, in order to produce liver damage. Tel- cky (1927) reported a number of cases of chloracne in persons exposed to chlorinated naphthalenes with a chlo rine content ranging from 14 to 53 per cent. He found that the lower the chlorine content the less the acne. Mittclstadt (1935) examined a number of cases of chloracne due to trichlor- naphthalene and reported a number of vague general complaints but nothing in the nature of serious disease. Re garding his animal experimentation, Lehmann (1919) reported that ani mals fed chlorinated naphthalenes re fused to eat after a time and that, whether poisoned by inhalation or by feeding, at death showed "peculiar" lesions in the liver. Fliim and Jarvik (1936) gave subcutaneous injections of enormous doses of chlorinated naph thalenes dissolved in paraffin oil to rabbits. The compounds used were as follows: . DSW 346089 STLCOPCB4084408 [Sep*. 19ST trichloir ere found mploints, igo, but ily, "Ab and we iic diges ts which y appear nsidering troubles oiy phe- >sure was ercas the r atrophy of higher eriments denes re- beyond ustry, in zc. Tel - jp-r -c^ses tO ti a chlor to 53 per wer the he acne, i number trichlorumber of nothing -sc. Re futation, iiat aniicncs re ad that, n or by eculiar" J Jarvik ctions of d naphi oil to cd were nl. 19, no. 71 EFFECTS OF CHLORINATED HYDROCARBON'S 285 1. A mixture of tri and tetrachlornaphthalene. 2. A mixture of tetra and penta. , chlomaphthalcne. 3. A mixture of penta and hexa: . chlomaphthalcne. In addition, sublimates from (2) and (3) were collected in oil and injected subcutaneously. ' None of the animals receiving (1) or the sublimate from (2) died, and even after 2 months were quite normal when autopsied. The first death in the ani mals receiving (3) occurred on the 12th day and the last died on the 26th day. Those receiving the sublimate from (3) were even more; severely affected. Autopsy in these animals revealed striking changes in - the liver, not, as described, entirely characteristic of acute yellow atrophy but sufficiently suggestive to cause the authors to con clude that "certain chlorinated naph thalenes or impurities contained in them are capable of producing yellow atrophy of the liver in the rabbit." At the beginning of their pa|x*r, Flinn- and Jarvik (1936) mention the fact that there have been three cases of acute yellow atrophy of the liver in men working with chlorinated naph thalenes but give no details in regard to them. These cases are undoubtedly the same as those described in the beginning of this paper. Cne may summarize the meagre literature upon systemic effects from these substances as follows: 1. With the exception of the men tion of acute yellow atrophy by l-'linn and Jarvik (1936) there arc no reports or even suggestions of serious effects upon human beings. 2. There is evidence (Telekj', 1927) that the degree of chlorination is sig nificant in relation to the production of acne. In the work of Flinn and Jarvik (1936) the compounds produc ing serious liver injury were the most highly chlorinated of those tested, though the chlorine contents as given by analysis vary surprisingly little. 3. There are no published figures upon the amounts of various chlorin ated naphthalenes in the air which will produce injury of any sort, and while the work of Lehmann (1919) and of Flinn and Jarvik (1930) point to the liver as a possible site of injury this indication rests upon such extreme dosage as to. fail to apply directly to human exposure. Experimental Work In appraising the possible toxicity of any substance met in industry it is first nccessarj" to determine the prin cipal route of alvorption. In the of the compounds under consideration there can be no doubt that inhalation is their chief means of entering the body. They are used hot in a great variety of operations and volatilize in varied degree. They are often applied in solution in such volatile solvents as carbon tetrachloride and toluene. The amounts reaching the air under such circumstances arc hardly detectable. It will however l>e shown that carlxm tetrachloride adds to the toxicity of the chlorinated naphthalenes and allied comixmnds, and if there is possibility of inhaling these compounds in other parts of the factory then inhalation of carljon tetrachloride adds a decided hazard. Under such circumstances solvents such as toluene should be used. : Observation in a number of plants causes us to feel that even though -T 75'-- DSW 346090 7w.|*auin T STLCOPCB4084409 ' "V Vi . : -v 286 JOURNAL OF INDUSTRIAL IIYGIEXE AND TOXICOLOGY [Stpi. 1937 workmen may be extremely dirty and careless, comparatively little of these waxes is eaten. They are tenacious substances, insoluble in water, and if they get on the hands they stick there and arc not transferred to the food. Skin absorption is the third possible means of entering the bod}'. It may occur but at best must 1h: slight when compared to the steady inhalation of finely divided or gaseous material in the air. tion. They thrive upon a diet very similar to man, and in the case of these chlorinated compounds it is possible that diet may be very .significant. Finally, their normal characteristics have becu described so well as to make the detection of abnormalities both easy and certain. Metkod of exposure.--The inhalation experiments were carried out in four large air-tight wooden boxes, each capable of holding ten nit cages, size t i- i *1 ;?. Fig. 1. Frout view and inflow end of two boxes with rat cages in place and doors open. Inhalation experiments are then the most iiniKirtant sources of information, but to them we have added a certain number of observations iqxm ingestion and subcutaneous injection of various compounds. Inhalation Ex/>erimenls Animats.--"White rats have been employed throughout. They permit the use of a large number of animals in a relatively small inhalation installa- 22' x 22' x 14', in two tiers of five cages each. When the exj>eriment was not in progress the doors were ojiened wide and the cages kept in place (figure 1). At the center of one end of eacli box --the inflow end- air was introduced .through a pipe 7 inches in diameter (figure 2). Each box was equipped with an individual variable-speed elec tric blower which blew the air through several feet of 7-inch pipe licfore enter- rol. 1 ing mete the 1 couk from defle pipe sure strea . At OUtfl' was filter a lar At the 7 of tl dum cially (figui dianr hold were that top o this i lengti into tight! pipe ( flask heate below top. side a voir a throu motio Intoc centig kept i time which Apt chlorii DSW 346091 Ttwryrrrrr STLCOPCB4084410 1937 very liese sible tank sties sake both ition four 3BCll size five was ned iace box cod ter ped Icctgh tor- roL 19, no. 7} EFFECTS OF CHLORINATED HYDROCARBONS 287 iug the end of the box. An orifice meter was placed in the pipe line, and the flow of air in cubic feet per minute could be adjusted and read off directly from a calibration curve. A vane deflector placed at the entrance of the pipe into the box was adjusted to as sure a uniform distribution of the stream of air to the two tiers of cages. At the opposite end of the box--the outflow end--the air from each law was exhausted through a 7-inch pii>e fitted with a damper and connected to a large central exhaust fan (figure 3). About 4 inches from the entrance of the 7-inch pipe into the box, the fumes of the substances listed were intro duced into the inflowing air. Spe cially designed pyrex glass flasks (figure 4), 7-J inches long and with a diameter of I5 inches, were used to hold the heated waxes. These flasks were made with a side arm and tula? that extended to the bottom. The top of the flask was ground, and into this fitted a short tube inches in length. This short tul>c was inserted into a large rubber stopper that fitted tightly into a hole cut out of the 7-inch pipe on the under side (figure 2). The flask in turn was placed in an electric heater made to cover it completely below the side arm and ground glass top. Rubber tubing connected the side arm with a compressed air reser voir and a gentle stream of air blown through the melted wax kept it in motion and assured uniform heating. Into each flask was inserted a long stem centigrade thermometer which was kept in place and could l>e read at any time above the 7-inch pipe through which it passed (figure 2). Approximately 30 gm. of pulverized chlorinated naphthalenes or 20 gm. of chlorinated diphenyl were placed in the bottom of each flask and melted in the electric heater. Fresh samples were used every other day, but it was often found necessary to add 20 gm. of new material even "after one run since so much had sublimed. Whatever the case, the collected sublimate was Fig. 2. Electric heater for maintaining chlorinated compounds at a constant tem perature in place at inflow end of box. always removed from the upper part of the flask and a clean top used each day. No sample was ever used for more than two runs. . The flask plus the contents was care fully weighed at the beginning of the run and at the end, and the loss in weight used to calculate the average 1 1 j.'V 'uyt *.w wKmtjssr* r >m**wf**z> DSW 346092 STLCOPCB4084411 iit iYTr*dlitiVrVt~'ii*--^ - ., j-.*-^iiiaLnA.llltfr1tT - -j| mf-, ,, -, 288 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sp<. 1937 pol. 1 amount in a cubic nigter of air per flowmeter readings. The figures ob ?r. Dog minute as determined by a series of tained were not absolute because of eggs ;1 slight variations in the air flowing T) through the boxes and because of begi deposition of material on the ther expt mometers and on the inside surfaces of chlo the box, but they checked well_ with 16tl direct .determinations through...air com samples. ,18tl Approximately 1 hour was allowed tive ?~i ;: for the wax in the flasks to melt and sun come to a constant temperature. At kill* that time the box doors were tightly loti closed, air bubbled through the flasks, and the blowers turned on. This was :* the beginning of the exposure period. Cor By means of rheostats on the fans and >3: dampers in the outflow pipes, the :.i amount of air flowing through the ;* .. boxes uas adjusted and an attempt was made to keep the four boxes as Fig. 3. Outflow end of two iioxes showing connections to exhaust system. - uniform as possible--usually between 165 and 175 c.f.m. Tri In the first group of experiments the following substances Mere tested: Pei 1. A mixture of trichlornaphtha- lenes plus a trace of tetrachlor- 90' napthalene. Chlorine content 1< 49.9 per cent. 2. A mixture of penta and hexachlornaphthalcnes. Chlorine Cl content 62.6 per cent. /N.I Fig. 4. Pyrex gtass flask 3. A mixture of 90 per cent penta and hexachlornaphthalenes plus 10 }>cr cent refined chlorin ated diphenyl. Chlorine con tent 63.0 per cent. 4. Chlorinated diphenyl. Chlorine content 65.0 ]>cr cent. The cominmuds M ere selected as rep resenting a certain range in chlorina tion and also ljecausc of their industrial importance. In each instance 80 ani mals were exposed, 10 rats being placed in each cage. They were fed Purina I* tt & e fc 1 I c 4 x f c DSW 346093 STLCOPCB4084412 tr Ml. 19, no. 7] EFFECTS OF CHLORINATED HYDROCARBONS 289 b- Dog Chow supplemented by lettuce, wax concentrations were somewhat of eggs, milk and cod liver oil. higher at the inflow end of the boxes. g This first group of experiments was Preliminary runs showed that once of begun on July 1, 1936 and the last properly adjusted, wax concentrations T- exposure to number 2 (penta and hexa- in the air remained very uniform from of chlornaphthalenes) was on November day to day, but to insure absolute rh 16th. The exposure to the other three safety readings of temperature, air iir compounds ceased upon November flow, etc. were made every night be ISth. On October 15th representa tween 10:00 and 12:00 p.m. as well ed tive animals were taken out of expo as on starting and stopping. At dif id sure from groups 1, 2, and 4 and were ferent times during the course of the At killed after 2 months on December experiment tests for free chloride were ly 15th, in order to see whether this clear made but were uniformly negative and as TABLE 1 >d. Conditions Maintained in Inhalation Experiment from Jult 1 to November 10 and 18 nd he MATERIAL CKHILSOS> CONTENT TEHP. AT. CONCENTRATION or AIR IK BOX TOTAL EX POSURE AT, dEaXily POSURE he ;pt % *c. Wlf./cu. m. ren^e hntr$ hour* as Trichlomaphthalcnes plus traces of *r tetrachlprnaphthalene................... 49.9 150-160 ,?-3i High 2.60 1896 16 Low 0.10 :hc Penta and hexachlornaphthalenes__ 62.6 1GO-170 1.16 High 2.19 1864 -16 Low 0.51 :ia- or- 50% penta and hcxnchlornaphtha- ?nt lenes plus 10% chlorinated diphenyl. 63.0 165-175 1.37 High 3.17 1896 16 Low 0.04 xaine Chlorinated diphenyl.................. . 65.0 165-175 0.57 High 1.19 1896 Low 0.23 16 ata lies nnOIl- period would bring about recovery in the affected livers. Animals from group 3 were similarly removed from showed that under the temperatures used no decomposition occurred. Table 1 shows the temperatures at exposure on October 4th and killed which the various substances were ine for examination on December 4th. held, the average concentrations per The average length of exposure was cubic meter of air, and the average cp- 16 hours daily for 6 days a week. exposures from July 1 to November ma- Each morning at about 9:00 exposure 16 and 18. rial ani- ceased, and between this time and The concentration of chlorinated naph 4:00 p.m. the rats were cleaned, fed, thalenes and chlorinated diphenyl in the ced weighed, etc. In order to secure uni air of workrooms.--Table 1 shows that riiia formity of exposure the cages were animals have been exposed to varied shifted on a regular schedule, since concentrations of the substances under DSW 346094 jywKtV..,',^Vr* STLCOPCB4084413 290 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY \Sept. 1937 ; test. The concentrations employed in question is passed over heated plntimay be regarded as fairly reprcsenta- num in an electrically heated quartz tive of industrial experience. Prior to tube and the effluent gas scrubbed in the initiation of inhalation experi- a column of glass beads moistened with ments a number of estimates of chlo- sodium carbonate containing a trace of rinated hydrocarbons in the air of dif- sodium sulfite. The beads are then ferent factories were made and the washed down and the chloride deter- 50CT10N concentrations chosen for inhalation experiments depended on these exami nations. The technic of analysis and 'the apparatus employed were the work of Frederick R. Millhiser and William F. Hemperly. The method and apparatus used for determining concentrations of chlorin ated hydrocarbons in air were adapted from well-known procedures. The air mined nephelometrically as silver chloride. Tebbens (1937) has recently de scribed a method and apparatus which should be equally satisfactory for this work. In figure 5 we show a dimen sioned sketch of the combustion tube and absorption apparatus as used by us in both our laboratory and field problems. The absorption tube is vol. 19, no. 1\ somewhat easi Tebbens's but devices are tl In both cas< >. rinated hydro acid and sul sodium carboi it\ In our case c apt to be ve: I less than 1 it i queutly the s I j* actually form so small that either gravim For this reasc s. .use the nephe i .is sensitive t t as 0.1 mgm. p i It is doubt r should exceei t conversion o *t pound to hj ri subsequent ai l unless the ve! low. Anothc is that the i l I* any cblorin: determined, distinguish b gases but det the results i i puted in ten At the pr< i formation as rinated napl different pin i instances tht repeated se the amount: those used i must be re The cotnl ratus suited t by Willson I i The equij>m< auction puinp DSW 346095 STLCOPCB4084414 m . . jj y * Hr! ' - - y-rii / : . ^-: . rr,-- .-,.. ~ --.: V : V-rrmv-'Vnri- i V- f ' 1 :& i- % tot. 19, no. t] EFFECTS OF CHLORINATED HYDROCARBONS 291 fS:somewhat easier to wash down than is have been exposed for 16 hours to an Tebbens's but the essentials of the two atmosphere constantly impregnated devices are the same.* with the substance under test, whereas In both cases conversion of the chlo human exposure is* usually a variable rinated hydrocarbons to hydrochloric quantity, intense for a short time and acid and subsequent absorption ns then negligible. It is our opinion at sodium carbonate should be complete. the present time that the concentra In our case concentrations in air are tions of chlorinated hjxlrocarbons used apt to be very low--the objective is in our experiments would be dangerous less than 1 mgm. per cu. m. Conse for workers in the case of compounds quently the amount of silver chloride above trichlomaphthalene in chlorina actually formed in the final reaction is tion. Fortunately it is easy to venti so small that it can not be determined late processes of manufacture which either gravimetrically or by titration. require these substances and to reduce For this reason we have been forced to air contamination practically to the use the nephelometric procedure which vanisliing point. Such treatment of is sensitive to concentrations as low the problem at once removes both the as 0.1 mgm. per cu. m. of air. possibility of systemic poisoning and It is doubtful if the sampling rate the anncyances that arise from cases should exceed 1 liter per minute as of acne. conversion of the chlorinated com pound to hydrochloric acid and its Results of Inhalation - Experiments. subsequent absorption are not efficient 1. Animals exposed to a mixture unless the velocity of the gas stream is of triehlornaphthalenes plus small low. Another precaution to be noted amounts of tetrachlornapthalene. is that the method is not selective-- Living animals were apparently en any chlorinated substance will be tirely normal. Autopsies performed determined. Furthermore it docs not near the end of exposure seemed to distinguish between solid particles and show slight swelling of the liver, and gases but determines them all alike and microscopic examination occasionally the results must, of course, be com showed swollen and hypergranular liver puted in ternis of total chlorine. cells. The changes were, however, At the present time we possess in never more than slight. formation as to the amounts of chlo 2. Animals exposed to a mixture of rinated naphthalenes in the air of 30 penta and hcxachlornaphthalencs. different plants, and in a number of No abnormalities were observed in the instances the measurements have been living animals. Rats were killed and repeated several times. Frequently autopsied every G weeks. In the first the amounts have been greater than animals sacrificed liver changes were those used in our experiments, but it observed. These were swelling of must be remembered that the rats cells, slight granulation and hj-aliniza- * The combustion and absorption appa- \ tion. In September and October these r&tus suited to field sampling is now made j conditions were somewhat more ad by Willson Products, Inc., Reading, The equipment includes flowmeter Pa. and J j vanced, and in November the process suction pump with a currying case. j became stationary. There were highly DSW 346096 STLCOPCB4084415 _-* --* r - *-* 292 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sep*. 19S7 granular cells, hyaline inclusions and mitotic figures, but no more than 2 months previously. 3. Animals exposed to a mixture of 90 per cent penta and hexachlornaphthalcnes plus 10 per cent refined chlorinated diphenyl. No abnormali ties were seen in the living animals. After 6 weeks the livers showed changes similar to those in the animals exposed to penta and hexachlornaphthalenes. These advanced in grade during August and September and then became stationary. 4. Animals exposed to chlorinated diphenyl. No abnormalities were seen in the living rats. After 6 weeks' ex posure there was slight liver damage which advanced during the next 2 months. The changes consisted in slight to moderate swelling of the liver cells, an increased granularity and many mitotic figures. Ilyalinization was always present as a result of inhalation of chlorinated diphenyl. Summary of the first inhalation ex periment.--In these experiments care ful observation of appearance, body weight, activity, blood, and urine showed no abnormalities of any sort. Yet after 6 weeks' exposure all the compounds with chlorination above trichlornaphthalene caused minor de grees of liver damage, and no changes whatsoever in other organs. There was no acute yellow atrophy or any thing suggesting it except that a slight degree of liver damage was always present and was quite clear in the liver sections examined microscopically. This damage had no detectable effect on the health of the animals. They held their weight,' ate and behaved normally, being in every respect similar to the many people who have been exposed to these compounds without illness of any sort. '.' The functional appraisal of the liver damage caused by certain chlorinated naphthalenes'and by chlorinated di phenyl.--There are no tests of liver function uscful in such minor degrees of liver damage as were produced in these experiments. Indeed the ani mals resisted the injury so perfectly as to display no abnormalities except upon histological examination of the liver. The situation was perhaps similar to that met in industry, where, barring acne, the health of workers in these compounds has been good with the exception of the fact that in iso lated instances jaundice has occurred which upon at least three occasions has gone on to acute yellow atrophy. During recent years this disease has been seen following administration of carbon tetrachloride, arsphenamine and cincophcn. In the case of carbon tetrachloride it is known that a low calcium diet and alcohol favor the pro duction of liver damage. For the acute yellow atrophy that occasionally complicates use of the other two drugs no cause can be assigned. One cannot produce acute yellow atrophy with arsphenamine, but somehow or other this now and then does happen to pa tients under antisyphilitic treatment. It occurred to us that something of the same sort might be involved in this problem. The human cases have been scattered and few. They have been isolated instances out of large groups of healthy employees who have had equal degrees of exposure. It was our idea that perhaps many of these people got liver changes such as existed in our rats, changes not recognizable through sol. 19, any m nation such i distur not a which this ) over 1 Ivn had ] slight we d< subst 6truc alcoh math chlor . per I nom to 0 0.75 T1 tube mals folio Rats 1. ehloi 10, 1 2. at 9 a (ha Fe DSW 346097 STLCOPCB4084416 woL 19, no. 7J EFFECTS OF CHLORINATED HYDROCARBONS 203 any means other than autopsy exami nation. If, upon the substratum of 8uch changes, they got an acute liver disturbance, acute catarrhal jaundice, not a very common disease but one which any of us may experience, would this relative^ innocuous disease go over to acute yellow atrophy? Knowing that our inhalation rats had liver changes, but changes too slight to cause recognizable symptoms, we decided to test their resistance to substances known to cause liver de struction. Carbon tetrachloride and alcohol were selected. Having infor mation that 1.0 ce. of carbon tetra chloride plus 1.0 cc. of ethyl alcohol per kilogram would kill 14 per cent of normal white rats, we reduced the dose to 0.75 cc. carbon tetrachloride and 0.75 cc. of ethyl alcohol. This mixture was given by stomach tube to the following groups of ani mals and with-the results found in the following tabulation. Rat* fed 0.7S cc. "per kgm. each of carbon tetrachloride and ethyl alcohol by "Stomach tube ' 1. Trichlomaphthalene plus trace of tetrachlornaphthalenc. Fed at 9:00 &.m.t Nov. 10,1936. 10 rats. No deaths. 2. Penla and hcxachlornaphthalcncs. Fed at 9:30 a.m., Nov. 10, 1936. 10 rats. 3 died Nov. 11th between 4:30 and 10:30 p.m. 1 died Nov. 12th at 3:20 p.m. 1 died Nov. 12th at 4:30 p.m. 1 died Nov. 13th between 9:30 and 11:30 a.m. 1 died Nov. 15th between night of Nov. 14th and 12:30 p.m. Nov. 15th. 2 died Nov. 16th between 10:15 p.m. Nov. 15th and 9:00 a.m. Nov. 16th (stiff). 3. 90 per cent penla and hexachlomaphthalcncs and 10 per cent chlorinated diphenyl. Fed at 10:00 a.m., Nov. 10, 1936. 10 rats. 1 died Nov. 10th between 5:00 and 10:30 p.m. ; ' 5 died Nov. 11th between 4:30 and 10:30 p.m. 1 died Nov. 11th between 4:30 p.m. and . 9:00 a.m. Nov. 12th. 2 died Nov. 12th about 1:00 a.m. 1 died Nov. 13th between 5:00 and 10:00 p.m. 4. Chlorinated diphenyl. Fed at 10:00 a.m., Nov. 10,1936. .10 rats. 1 killed Nov. 10th at 10:30 p.m. (almost dead). 2 died Nov. 11th between 4:30 and 10:30 p.m. . 1 died Nov. 12th before 8:30 a.m. (stiff). 1 died Nov. 13th between 9:30 and . 11:00 a.m. 1 died Nov.. 16th between 10:15 p.m. Nov. 15th and 9:00 a.m. Nov. 16th (stiff). Controls: Fed at 9:30 a.m., Nov. 12,1936. 10 rats. 1 killed Nov. 13th for normal liver. This tabulation summarizes into the facts that: . * 1. No normal rats were killed by carbon tetrachloride and ethyl alcohol. 2. No trichlomaphthalene exposed rats were killed, and this finding agrees with our inability to find lesions of moment in the livers of the animals that inhaled this substance. 3. The penta and hexachlorinated naphthalene, the mixture of these with 10 per cent chlorinated diphenyl, and finally the latter substance alone seem to have produced conditions lowering the resistance to an agent capable of producing serious liver disease. 4. The sole lesion produced by this test of liver function was acute yellow atrophy usually accompanied by jaundice. This test of liver function was ac complished with a substance which itself is an organic chloride and curi ously enough it is the only substance we were able to find that was effective. DSW 346098 STLCOPCB4084417 j 294 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. 1957 r1 re - v4 In animals with the minor degree of liver injury which has been described we were unable to produce acute yellow atrophy or any variety of liver effect with arsphenaminc, cincophen, butyl signs of liver injury' will be many months in returning to normal. The effect of high concentrations of trichlomaphthalenes with traces of tetra- [ \ Ii. I. fl in rs or cl tc chloride, ethylene chloride and tetra- chhrnaphthalcne.--The first group of i th . chlorethylene, but carbon tetrachlo inhalation experiments showed that t Ul ride wras uniformly effective in dis this material in concentrations averag tr -i Vi closing the existence of liver damage. ing 1.31 mgra. per cu. m. of air was relatively innocuous, judged both by Recovery from liver damage folloiving direct observation and by the carbon P< removal from exposure.--Animals ex tetrachloride test. This is an in T posed to triclilornaphtfcalenes plus teresting fact since such compounds 1 at '2 traces of tetrachlomaphthalenc being cause acne, though less potently than bi ?>< practically normal on removal from substances of higher chlorination. P< exposure need no consideration. In In order to explore the matter further * the case of the penta and hexachlor- one of the inhalation boxeswas arranged cc n< TABLE 2 orConditions Maintained during Inhalation of High Concentrations Trichlornaphthalenes plus Tetrachlornaphthalene C< 'i _ MATERIAL nur. It. conctktratxok . rrer ass ax sos Trichlornaphthalenes plus traces of tetrachlornapht halcne c. tng.fcv. m. 137-200 10.97 range High 10.49 Low 5.78 TOTAL AT. DAILY lovre 1232 houra 16 ri P at naphthalene, rats after 2 months' re so that fumes from four glass contain U: moval from exposure still showed ers were delivered to the air line instead 0 swollen liver cells, increased granu of one. This resulted in the conditions SI larity, hyalinizalion and mitotic fig shown in table 2. The animals sub t m 1 ures. The condition was not advancod jected to these conditions showed no as compared with rats killed at the clinical effects of any sort. After 1 Ii i w tl time of removal from exposure but on month the liver cells were slightly i ai the other hand 2 months were insuffi swollen and over-granular and there si 1 cient for recovery. were occasional mitotic figures. These The same findings were true of the changes were similar to the early tl fc mixture of penta and liexachlorinated effects of more highly clilorinated & /-naphthalenes and chlorinated diphenyl compounds, and progressed only ai and for chlorinated diphenyl alone. slightly during the third and fourth e: Apparently the changes induced in months. AVhcn rats in this condition kj the liver cells by these substances are were given carbon tetrachloride and ft ]! exceedingly persistent and one must alcohol, in some instances their livers expect that an individual showing any showed massive central necrosis and i w tu i d DSW 346099 STLCOPCB4084418 90t. J9. no. 71 EFFECTS OF CHLORINATED HYDROCARBONS 295 in others this did not develop. Fifty the liver after 35 days of freedom from rats were used in tills experiment and inhalation. It is thus evident that ' one may conclude that while the tri- penta and hexachlornaphthalenes are chlomaphthalencs are in no degree as markedly toxic compounds and that toxic as those of higher chlorination recovery from their effects is extremely they are not entirely free from effects slow. , v; upon the liver if high enough concen trations are inhaled over long periods. The effects of penta and hexacklor- naphthalenes, the mixture of these with The effects of high concentrations of 10 per cent chlorinated diphenyl, and of penta and hexachlomaphlhalcncs.-- chlorinated diphenyl alone, vrhen inhaled There can be no doubt as to the dam in low concentrations through an 8-hour age done the liver by these compounds day instead of a 16-hour day as in the but in the concentrations so far re first experiment.--Since steady human ported no symptoms were caused that exposure to any of the compounds could be recognized clinically and tested would invariably be for 8 hours nothing approaching acute yellow rather than 16-hour periods, a further TABLE 3 Conditions Maintained dobing Inhalation of High Concentrations of Penta and Hexachlornaphthalenes - IUTKKUL Penta and hexachlornaphthalenes......... Tucr. c. 137-195 AY. COKTENTZATICS j TCTaL AY. SAT-T Or A1B IN BOX . (EXPOSCHE EXFOSUHE 1 wig.feu. m. ranfft Wt hour* 8.88 High 14.0 Low 5.75 603 16 - : f - t'" atrophy occurred except through the use of the carbon tctracliloride test, On December 1, 1936, SO rats were subjected to the conditions summarized in table 3. Tliis experment was terminated on January 21. All of the animals lost weight and appetite and deaths began after 8 days of exposure. Fifty-five rats died, most of them heavily jaundiced, 8 were killed for microscopic examination, 9 were killed by the carbon tctracliloride test and 8 lived through the period of exposure. The livers of the animals killed for examination showed marked fatty degeneration, central in type with necrosis of liver cells. Surviving animals showed pronounced changcs'in inhalation experiment \vas arranged under the conditions shown in table 4 which are quite comparable to those in table 1 except for the shorter inhalatiou periods. Eighty rats were used for each of the three compounds tested, None at any time showed the slightest evidence of illness. Microscopic exanimation beginning after 6 weeks' exposure showed swollen liver cells, excess granulation, hyaline inclusions and occasional mitotic figures. These changes did not progress and were very similar to those in the animals exposed for 16 hours under the conditions set forth in table 1. The carbon tetrachloride test was uniformly fatal to them and one must conclude that con- i I. i f i DSW 346100 ii STLCOPCB4084419 .fc'n'WfriaiVjri aar tti,>i,irj.ii. .. , Wt ftr itrariy/rtfHr,!' 296 JOURNAL OP INDUSTRIAL HYGIENE AND TOXICOLOGY fSept. 1957 centrations of these compounds such men never inhale enough of any of -i as were employed cause a certain de these substances to get acute yellow gree of liver damage even if inhaled for atrophy. They may, however, acquire but 8 hours daily. This injury is a substratum of liver damage upon resisted successfully by the rats just as which acute yellow atrophy may de was the 16-hour injury but it is none velop. Experience in a number of the less there and destroys the ability plants has shown how easy it is to of the animal to resist the carbon reduce concentrations of these com -a tetrachloride test. pounds practically to the vanishing r point, and every effort should be made Summary of inhalation experiments. to attain such conditions. 1 The findings that have been described briefly will be amplified upon the Gross Feeding Experiments pathological side in a further paper by The various compounds used were Dr. G. A. Bennett. What has been ground as finely as possible and mixed given is, however, sufficient to indi with a standard balanced ration for TABLE 4 Conditions Maintained during Inhalation of Low Concentrations of Three Compounds during 8-Hour Instead of 16-Hour Periods BLATXRIA1, TtlfP. AT. CONCENTRATION Or AIR IN BOX TOTAL AT. PAILT EXPOSURE EXPOSURE *c. *9 ronpc \ A.-** Penta and hexachlornaphthalenea......... 149-193 1.44 90% penta and hexachlomaphthalenes plus 10% chlorinated diphenyl.......... 150-197 1.66 Chlorinated diphenyl.............................. 153-174 0.93 High 2.58 Low 0.42 High 3.30 Low 0.56 High 3.23 Low 0.03 920 912 .920 8 8 8 cate that compounds more highly chlorinated than trichlornaphthalene are capable of causing liver injury when inhaled steadily in quite low concentrations. It is an extraordinary thing that even the most searching examination fails to show' injury in any other region. It is not easy to grade the toxicity of the different compounds tested, but the chlorinated diphenyl is certainly capable of doing harm in very low concentrations and is probably the most dangerous. Industrial experi ence combined with these experiments make it appear probable that w'ork- the white rat. The food was placed in a single container, at which the 10 animals in a cage had an equal chance, the amount of the compounds added being reduced as the number of rats lessened during the feeding period. The experiments were designed to give an idea as to the possible toxicity of the compounds selected and, if toxicity was observed, some idea as to the site or sites of damage. The experiments were successful in both respects, and indeed one may anticipate that future appraisals of the possible toxicity of chlorinated hydro- vol. it carbo feedii rate : sary essen in tli by lx diffei seem Iso fs ever Ti tetra< on until ning to t and thre anic whii loss was dea' spir tior l slig of g 3 Fct dO; All wre; 29, log aff inf sic th wi Ft dc DSW 346101 V STLCOPCB4084420 9at of low lire pon de- of , to omling iade were ixed i for tEE .SJULT WU loura l 8 8 ilaced he 10 lance, added f rats leriod. o give :ity of racity be site sful in 3 may ; of the hydro- ' i'.' : *oZ. 19, o. rj EFFECTS OF CHLORINATED HYDROCARBONS 297 carbons may often be made by simple rats had died. The last one was obvi- feeding and do not require the clabo- ously ill and was killed for autopsy v ' rate apparatus and the expense neces- examination. All animals lost weight sary for inhalation experiments. The from the beginning and were ill. At essential reason for this opinion resides autopsy the liver alone was affected, in the identity of the lesions produced the lesions observed being similar to by both methods, and the fact that the those that have been described for different compounds so far studied, tetra and pentachlornaphthalencs but seem to arrange themselves identically worse. so far as toxicity is concerned which- 90 per cent penta and hexachlor~ ever way they are administered. naphthalenes and 10 per cent chlorinated Trichlornaphlhalcne plus traces of diphenyl.--Feeding began May 4, ielrachhrnaphthalene.--Feeding began 1936 on a 3 gm. dosage. On May on May 4, 1936 and continued 16th feeding was stopped but all until November 2,1936. In the begin- the animals went on to death, the last ning 3 gm. of this mixture were added dying on June 8th. An autopsy the to the food for 10 rats each day, liver lesions were extremely severe and and this concentration was maintained of the usual type, throughout the experiment. All the On account of the high toxicity of animals were killed except the last the 3 gm. dosage, four rats were given winch died on Nov. 2. There was no a 0.5 gm. dose every other day. Feed- loss of weight and no appearance of ing began June 24, 1936 and the last wasting illness of any sort. The single animal was killed Sept. 11th. There death Wits due to some variety of re- were no deaths but all the animals lost spiratory infection which had no rela- weight. At autopsy the liver as usual tion to the material inhaled. was the single organ affected, the Histological examination showed lesions being characteristic and ex slight changes in the liver but nothing tensive. of great significance. ` ' Chlorinated diphenyl.--Feeding be- Tctra and pentachlornaphthalencs.-- gan May 4, 1936 on a 3 gm. dosage Feeding began on June 29, 1936. A and was discontinued on May 10th. dosage of 0.5 gm. daily was employed. Seven of the 10 rats were dead by May All the animals sickened gradually and 12th. The three remaining rats were cither killed or died by August gained in weight but were sacrificed 29, 1936. for autopsy purposes on July 8th. At autopsy both grossly and histo- The liver changes began at once, logically the liver was the single organ There were no changes in other organs, affected. The liver cells showed swell- A second group of 10 rats was fed a ing, hypergranulation, hyaline inclu- much smaller dose--0.5 gm. every sions and vacuolation. Here and other day. Feeding began May 20, there necrotic cells were found. There 1936. The first rat died on May 29th was a tremendous accumulation of fat. and four more before June 24th. The Penta and hexachlomaphthalencs.-- remaining were sacrificed. Those rats Feeding began May 4, 1936, a 3 gm. that died showed losses in weight, dosage being used. By June 6, nine while those sacrificed had recovered DSW 346102 yv * V VU ' K"T' t [ ? { iii fir lr- i i l! f 1 i !I V i ! t \ ! i It 5 i i i i l STLCOPCB4084421 ^ .5 , 1 | |_ | - i: 1 298 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY (Scpl t93T ' .. ,, their initial loss in weight and were and rabbits, the dosage being calcu- gaining. The liver lesions were similar lated on the basis of 4 mgm. per cu. m. to those found in rats fed penta and of air. Again similar results were hexachTomaphthalcncs plus 10 per obtained. In all such experiments cent chlorinated diphenyl but not so there must of necessity be differences marked. in the degree of effect but invariably / ,, the liver was the sole organ affected Summary of gross feeding expert- anj the lesions Were those already ments.--Ol the various materials fed described many times, rats in large doses triehlornaphthalene plus traces of tetrachlornaphthalene Discussion was quite innocuemsr Tetra and pentaclilomaphthalcne showed definite liver damage. Penta and hexachlornaphthalenes caused a similar grade of injury. The addition of chlorinated diphenyl to penta and hexaehlornaphthalcncs increased the toxicity. Chlorinated diphenyl alone produced liver lesions but in the dosage used n as less effective than-when mixed with highly chlorinated naphthalenes. In no c.ise did the compounds used prQdqqe.g.cute yellow atrophy but the lesions observed indicate this might be possible if one found a dosage which could act for the proper period of time. These experiments leave no doubt ^ ^Cj ^jje possibility of systemic effects from the chlorinated naphthalenes and chlorinated diphenyl. As in the case fr-,e effects upon the skin, the degree Qf chlorination seems to determine the 6ysteinic toxicity, and it is a striking thing that when triehlornaphthalene is reached systemic effects are never marked and are produced with the greatest difficulty. It is most rernarkabIe> too, that all the compounds tested attack the liver and the liver a]0ne. During the past few months we have determined the organically combined chloride in the livers of ani Feeding Precise Doses by Stomach Tube The compounds employed were sus- pended in gum acacia. In figuring the dosage the total amount a man of 50 kg. would inhale in an 8-hour day nials very severely poisoned by penta and hexachlornaphthalencs but have found no increase over normal figures, thouSh the livers- as determined histologically, were very severely affected. assuming an air concentration of 20 mgm. per cu. m. was first calculated and reduced to milligrams per kilogram. The rats and rabbits received this dose each day. The compounds used were those employed in the gross feeding experiments and the results were essentially similar though the lesions were less severe. Subcutaneous Injections The same gum acacia suspensions were injected subcutaneously into rats At the Present tuue wc are conducting ^halation experiments on a chlorin- ated diphenyl containing 55 per cent of chIorine instead of 64 Pr cont " in the case of the experiments reported in this and on a compound with a cUorme content betwccn tn ftnd tetrachlornaphthalene. We are also determining the degree to which the diet may increase or decrease toxicity, this being suggested by similar work upon carbon tetrachloride, In the basis of these experiments of. is, and o differe rooms taiuly that t more of til naphi comp are many plant bcem 20 ye fact been . hum; Time chan; but 1 safe, arra: hyui safe-1 lead Con J i i i Fin Led 'juw M1^. DSW 346103 \t STLCOPCB4084422 ana *. I- aa. re xs es iy ed dy ibt cts nd ase rec the ing e is ver the irV ads iver iths ally animta lave ires, istoled. ling rrincent it as Tted with and also i the 'city, work nents iw,r;r r,y,> ->-tt f -' -^^t-iV,Jf^-'--~i,T'-~',*--''-'i-~''^vfr~)i'i'^f -rrrViiyM'iY'iiw` ir'r'; iiM-i~i--- --- wol. 19, m. 7\ EFFECTS OF CHLORINATED HYDROCARBONS 299 and on many field determinations of pounds, these substances are very different compounds in the air of work little toxic and operations employing rooms, it appears safe and it is cer them can easily be safeguarded. It tainly easily attained, to ventilate so may be argued that where possible that the air breathed does not contain trichlomaphthalene should be used, more than 0.5 mgm. per cu. m. of any but this compound will cause acne and of these compounds above trichlor- if employed very carelessly might do naphthalene. In the case of the latter more. Furthermore, higher chlorina compound concentrations of 10.0 mgm. tion is often essential for highly prac are permissible. We know from tical reasons. The solution consists in many examinations in many different -thorouglily adequate ventilation plus plants that such concentrations have good housekeeping around all wax been greatly exceeded during the past 20 years, and we are conscious of the fact that our rat exposures have been inexorably constant whereas human exposure is never so ordered. Time and careful observation may change these opinions as to standards, but today we are convinced they are safe. Impregnating tanks and other arrangements utilizing the chlorinated hydrocarbons are easy to hood and to safeguard. Compared with benzene, containers. . ; A final word of caution bears upon the use of carbon tetrachloride as a wax solvent. Obviously this compound adds readily to the toxicity of the highly chlorinated waxes. If carbon tetrachloride is used, ventilation should be excellent, but in our opinion it would bo -better to dispense with car bon tetrachloride and depend on other solvents, especially upon those con lead tetraethyl and many other com taining no clilorine. BIBLIOGRAPHY Cocrtois-Scffit: Etude sur 1'intoxication professionnellc par 1c trichloronaphtaline. Ann. dc mf-d. Ifgale, 14, 422 (1934). Abstr. of paper by Tocraixe, A., and Mxtrel, B.: Dermatoses professionnelles par la naphtaline ct ges derivf-s. Prat. md. franc-, U 335 (1934). Flint,', F. B., and Jarvis, N. E.: Action of certain chlorinated naphthalenes on the . liver. Proc. Soc. Expcr. Biol. & Med., 95,118 (1930). Lehmann, K. B.: Kurzes Lehrbuch der Arbcits- und Gcu-erbehygiene. S. Hirtcl, Leipzig, 1919 (p. 251). Mittelstadt, O.: Gewerbeschadigungen durch Ilaftax (Trichlornaphthalin). Inaug. dissert., Jena, 1935. Tebbexs, B. D.: Portable combustion ap paratus for. field determinations of chlorinated hydrocarbons. This J., 19, 204 (1937). Telekt, L.: Die Pernakrankhcit (Chloraene). Klin. Wchnschr., G, 897 (1927). Tocraixe, A., Solente, Mxtrel, B., anb Aubkun: Cinquante-quatre eas de dermatites par trichloronaphtaline. Bull. Soc. dermat. et ayph., ff, 205 (1934). ' r. r i. fi i > i * f> i r f \ I i i t. DSW 346104 STLCOPCB4084423 300 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY JSspl. 1931 DI6C08SI0N ' Dr. Cecil K. Drinker: We have had incline them to. First of all I shall ask ~ quite a long morning, but since Dr. von Oet- Dr. Sayers if he will open the discussion . - 'l-s, yyja y jj^gpn f0 leave, I am going to ask him for us. : to say a word. ; ;; . Dr. R. R. Savers (Chief, Division of " 'i, A*' Dr. W. F. vox Oettingex (Director, Industrial Hygiene, National Institute of Haskell Laboratory of Industrial Toxicol-. Health, U. S. Public Health Service, Wash ;;**gy, Wilmington, Delaware): I wish to con-: ington, D. C.): Dr. Drinker, Ladies and 'gratulate Dr. Drinker and bis group on the* Gentlemen: Ttgave me a great deal of pleas very interesting and excellent work on the ure to have the opportunity to listen to the subject. I also wish to congratulate the . excellent and interesting discussion and Halowax Corporation on the fact that they presentations made this morning. Dr. didn't spare any effort to elucidate the prob Drinker, and I might add, the members of lem ao that the dangers which apparently the Halowax Corporation, have discussed are connected with the use of this materia! this matter with us, as well as the manu can be controlled. facturers of the' diphenyls. I personally believe that there is no toxic We have been doing some work but not - material which cannot be used safely if it is nearly as extensive as that carried on here. handled properly. In order to handle such The work that we have been doing seems to materials properly during the different oper confirm the work that Dr. Drinker has car ations it is absolutely essential to be famil ried on. I think there are certain parts of it iar with the toxicity and especially with the that we can very well keep in mind. ^ mechanism of the action. Since there is no We are dealing wilh toxic substances, but animal which corresponds in all its physio we are dealing with toxic substances each logical characteristics to the human being and every day ifrsindustry--harmful sub it is important that such compounds be stances, hazardous substances. That these studied with differen^species of animals so can be controlled is. well known, no matter that one can get a croES-section of the poten what they are, and that we can use them and tial dangers. use them in a safe manner. Dr. Drinker In addition, this fact illustrates the im has called your attention to the fact that portance of the pre-employment and peri this apparently has been done and can be odical examination of workers in such work. done in any of the plants where halowax is As was pointed out by Dr. Drinker, there used. I have information from one or two are individuals who are apparently more of the other men who are in the audience susceptible to certain toxic agents than that in plants where damage has been done others. On the other hand, we have to try --skin damage and apparently liver damage to detect the very first signs of incipient to some of the workers--the manufacturers .. poisoning in order to prevent more serious have since corrected the conditions and ap damage. In the present instance it is very parently have adequate engineering con difficult to find these very first symptoms trol supplemented with adequate medical because there arc no adequate methods, but control. I trust that in time the scientific profession After all, the proof of the pudding is in will supply the medical profession with the eating. If the man docs not get the dis adequate methods which will allow the ease your engineering control is successful. : physician to determine incipient damage of If he does get the disease, no matter what the organ before serious clinical symptoms you have done in the way of engineering, become manifest. you haven't been successful. We must go Thank you. hand in hand. Neither profession alone Afternoon Session can be succeasful. We have got to work together whether we like it or not. I hap Dr. Cecil K. Drinker: In this discus pen to like it. sion I will call on one or two individuals and There is one other thing. As far as mate I shall expect others to speak as their notea rials are concerned I think we ought to be ol. 19, * mart enc cessfully. : * adapted f1 it. Anotl vious to tl was Damn pproximi ay appro never just It might hi were quite happened with this r electric ca armor on t! and was be proximate! to a steel 1 bottom of t; inspecting : bide cap-lai the fire kill' mine. Mat Here we Now we hai due to the evaluate the I am- inforn not just sur flammability chlorination also increa; creases, acci think that c! have these h control then we can. Perhaps w are better ev present time better. I an submarines, i non-flammab: of their electr Dr. Cecil ` you care to si Dr. Alber of Occupatie: necticut Dcp: Conn.): Dr. I anything that this material j SW 346105 STLCOPCB4084424 37 tall ask cussion . ision of itute of s, WashLies and of pleasn to the ion and 3g. Dr. nbers of iscussed e manu- but not on here, seems to has cartartsof it d. nces, but ices each iful sub hat hese io ter them and . Drinker fact that id can be alowax is ae or two audience oeen done it damage zfacturers is and sp ring con e medical ding is in et the disiuccessful. -tier what ginecring, e must go lion alone t to work t. I hap- ar asmateught to be j- 1 pol. IS, iu). 7] EFFECTS OF CHLORINATED HYDROCARBONS 301 smart enough to use every one of them suc cessfully. If this material is particularly adapted for a certain purpose we should use It. Another material that was used pre vious. to this for insulation purposes, which was flammable, caused a disaster in which approximately 167 men lost their lives. I ay approximately 167 because they were never just sure whether it was 167 or 16S. It might have been one Gr two more but they were quite sure that 167 lost their lives. It happened when they had insulated a cable with this material. They had an armored electric cable. It was covered with lead armor on the outside. It was 1200 feet long and was being lowered into a mine shaft ap proximately 3000 feet deep. It was lashed to a steel rope. It slipped and fell to the bottom of the shaft. When the foreman was inspecting it he set it on fire with his car bide cap-lamp. The carbon monoxide from the fire killed those men that were in that mine. Many of course escaped. Here we have one hazard, a fire hazard. Now we have another one, a health hazard due to the toxic materials. We have to evaluate them. Certain of these materials, I am informed, are also flammable. I am -not just sure how flammable they are but flflTTiSisbil'ly - probably -uccrraBS? as y*mr chlorination increases. But your toxicity also increases as your chlorination in creases, according to Dr. Drinker, and I think that checks with other findings. IVe have these hazards to balance but we can control them. I feel quite confident that we can. Perhaps we can find other substances that are better even than this material. At the present time 1 am advised that we have no better. I am advised that in ships, such as submarines, it is quite important to have a non-flammable substance for the insulation of their electrical wire. Dr. Cecil K. Drinker: Dr. Gray, would you care to 6ay a word? Dr. Albert S. Grat (Director, Bureau of Occupational Diseases, State of Con necticut Department of Health, Hartford, Conn.): Dr. Drinker, I don't think there is anything that I can say except that we used this material in Connecticut and we had a number of so-called cases. All I can Bay is a confession of ignorance on our part at that time and I was very glad to see that your digging into the literature as thoroughly as you have hasn't elicite3 any further infor mation than we were able to get, basically. About all we could find was about the two cats that our friend, Lehmann, experi mented with. We got in touch with him and he confessed that the amount that he had given the cats and his method of determin ing it were probably subject to very serious scientific criticism, and we agreed with him on that point. We felt, and I am very glad that it is what you feel as a result of your experiments, that if we put in an efficient ventilation sys tem sufficient to prevent the dermatitis, wc probably wouldn't have liver damage. That is what we did entirely empirically. I think that is about all I have to eay. I have been delighted to be here and to have as many members of my staff here as I could jack out of the office. Wc have been de lighted to listen to the discussion. Dh. Cecil K. Drinker: May we now make the discussion general and those who have-questions please volunteer. Mb. Manfred Bowhitch (Director, Division of Occupational Hygiene, Massa chusetts Department of Labor and Indus tries, Boston, Mass.): I would like to second very strongly what Dr. Sayers has said with regard to the approach to this problem in proper control rather than by prohibition, which seems to me wholly unnecessary not only in this case but in the case of other toxic substances with which wc have to deal. The problem of proper ventilation seems to me relatively simple from what I have heard of the situation thus far. The problem of maintaining that ventilation properly does not seem to me quite so simple. I think it is going to be quite necessary that there should be a very adequate inspection of the plants using the materials and I can assure you that that vrill be the case here in Massachusetts. When this trouble first broke in this state a little over a year ago we issued a quite strongly w'orded warning letter to all plants using these substances and it has all along il i iv tt i. t- Ii: ii t ttr i ! i i t \t t itl iV is r t DSW 346106 STLCOPCB4084425 mass J J ft-; J --1 J ' * V .-a 4 l k 302 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept.mT been my plan to follow that up with & fur ther letter bringing the situation as wenow know it, as a result of Dr. Drinker's work, to the attention of users in this state. In that letter we shall unquestionably advo cate the concentrations that Dr. Drinker has suggested this morning. . V----,,.. One point that I think is worth comment ing on in that connection is the question of identification of the substances. It is ex tremely important from the state adminis- trative point of view that employers using these substances should know what they are using. They are identified at present only by numbers. If we list those numbers in a warning letter which we send out there are likely to be changes in those numbers. The Halowax Corporation is a progressive con cern and it is going to be putting out bigger. and better halowaxcs all the time. The company's cooperation in this present inves tigation has been such that I feel assured that they will take the proper steps to see that we in the state offices and also the users of the products will know what we are using. . I wonder whether Mr. Brown would pare to say any thing about that. -V Mn. S.iXDrojtn Brown (President, Halowax Corporation, New York, N. Y.): There are some aspects of this situation on which I think I can enlighten the medical and state and civic authorities, with respect to the commercial and practical aspects. If you go into the research laboratories of any large chemical manufacturing company today you will find anything from one to a thousand different new chemical products which have not yet been put on the market. Some of those may or may not be toxic. The problem so far as the chemical manu facturer is concerned is a question of timing. You have heard this excellent presentation given this morning by the Drinker brothers as to the work that they have done here. Should you take a product of which you have developed, say, 5 or 10 gm. and Bpend $50,000 on research to determine whether or not it is toxic or should you wait until you have determined whether you have a market for itT If you are producing only one hundred substances a year you can see that that would run into boxcar numbers in the way of dollars and cents before you ever sold any. Tbat is the problem we have had in': this case. It has been on the market for 25 years. Until within the past 4 or 5 years there has never been any intimation that it would cause any systemic effects. Thou sands and thousands of workmen have dealt with millions and millions.of pounds of cer tain of these materials, particularly the tri- chlomnphthalcnes. Then we come to the higher stages, combined with chlorinated diphenyl and other products, and suddenly this problem is presented to us. We had asked various authorities in terested in public health, going back over a period of 15 to 20 years, to investigate it but there wasn't much enthusiasm for it. Mr. Bowditch suggested that we take it up with the Drinker brothers at this institu tion, which we did. You know the results of that work. Now so far as these changes are con cerned, they are beyond our control to a certain extent. We will manufacture a product--let's call it 1234. It has certain chemical and physical characteristics. It is supplied is a esMe manufacturer. It is composed of certain constituents. There may be some tetrachlornaphthnlcne, tri- chlomnphthalcnc, paraffin, a little pitch or bitumen, and possibly some chlorinated diphenyl. It does a certain job but he wants it to a little more plastic or he wants its viscosity or the specific gravity changed. Possibly by a change in those constituents of only I per cent we can get that particular property. - We can't sell it to him as the same product so we put a new number on it. Basically,1 however, if the variation in the chlorinated naphthalene or the chlorinated diphenyl constituent hasn't changed, the toxic property of that will not change. When it comes to a question of cooperat ing with the state authorities in that con nection, if there were some major change made in a product we would have no hesi tancy in advising them and we would also advise our customers. Virtually every con sumer of these materials at some time or another has been given their technical or chemical designation along with their vari ous properties, whether they be physical or chemical. ,. Those are some of the practical problems `rVV5:'\ v.`v.-V-sC- DSW 346107 STLCOPCB4084426 `tfarjii'ii pot. 19, no. 71 EFFECTS OF CHLORINATED HYDROCARBONS 303 ; I ;. - * ' *' ' with which all manufacturers of chemicals are confronted today, particularly in the aynthetic organic field where the development is so rapid that our sales departments can't even keep up with the research departments sometimes, in knowing what they are doing. Mb. F. R. ICaimeb (Assistant to Manager, York Wireworks, General Electric Co., York, Pa.): I am certainly pleased to have this opportunity to 6ay a few words with reference to the experience we have had at our York plant. I perhaps should say that again in this case experience alone has been the best teacher. I have lived with the problem at York with the men who went through the experience from its beginning. It is only 1) years ago that we had in the neighborhood of 50 to 60 men afflicted with various degrees of this acne about which you all know. Eight or ten of them were very severely afflicted--horrible specimens as far as their skin condition was concerned. One man died and the diagnosis mar have attributed his death to exposure to halowax vapors but we are not sure of that. There was an atrophied condition found as a result of the autopsy but we are not definitely sure that it was or was not connected with his work. Knowing the man as I did when he was employed, with the superficial examination that he had, he appeared to me very thin, pallid in his appearance, and I would not say from my poor knowledge of the physical make-up of the human being that he presented a healthy appearance. However, it was only for a 6 months' period from the time of his employment that he complained of this constipated condition and we advised that he see his home physician. It rapidly developed to the point where he was in the hospital and in a very short time he died. More serious than that perhaps is the fact that we had 50 other men in very bad condition as far as the acne was concerned. The first reaction that several of our executives had was to throw it out--get it out of our plant. They didn't want anything like that for treating wire. But that was easily said but not so easily done. Wc might just as well have thrown our business to the four winds and said, "We'll close up," because there was no substitute and there is none today in spite ofall the efforts we have made through our own research laboratories to find one. >. But we did develop--and I was most closely associated with it--and set up a routine for bringing these men back to nor mal health conditions. A number of them were sent to Dr. John H. Stokes and to Dr. 0. H. Perry Pepper of the University of Pennsylvania Hospital, and the others to Dr. Isaac R. Pels at Johns Hopkins, Through their recommendations and studies we employed a trained nurse and two local physicians and you might say established a small hospital and its facilities at the plant, Through the application of quartz light, x-ray, mechanical removal of comedones and the treatment of pustules that de veloped in later stages, an utterly strict routine where the worst cases were adminis- tered to each day for a period of 15 to 20 minutes, another group who were less seri- ous three times a week, and still another group once a week, wehn'p in this yes*- and a half brought each and every man back to a normal skin condition. Those who were very seriously afflicted do show scars, but otherwise their skin is as healthy in appear- ance as my own. I tell you we are very proud of the fact that they are still all cm- ployed and the amount of halowax that we are using today is even greater in quantity and in types than we were using a year and a half ago. With the adequate ventilation system we- have installed, with the routine for change of clothing from street clothing to work clothing when they come to work and the reverse of that process, with the assurance that a shower will be taken before the street clothing is again put on, we have found no recurrence of this skin trouble. Each and every man working with halowax products, cither from solution, from solid compounds or handling the wire insulated and treated with it, is examined twice yearly with a coin- pletc physical examination, including blood analysis and efforts to determine any liver damage. However, there is the point which was very definitely brought out this morning, We do not know as yet when this thing starts. I believe it would be of great help > l L i 5 j. 4. i ; i \ it t i )t l DSW 346108 STLCOPCB4084427 304 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY t&pt. 1937 | ' :." ' - V - -' i to va all in industry if some very funda Springfield, Masa.): Do I understand you mental work was done on humans, as Dr. to say that those men who were afflicted Jones mentioned before we came into this are back on the same job? .. J ' meeting, some control in fundamental work to determine some method whereby we may Mb. F. R. Kaiuer: They all returned to determine the inception of any liver dis normal skin health, as I say, and are work order. - - ; O- . . ' ing on the same job. . . . We have had our men examined in groups three times since the trouble developed and Db. Cecil K. Drinker: Dr. Schwartz, nothing has shown up in any one man. We you have seen a good deal of this general have learned and appreciate the fact that we subject. ' ' .. must handle hazardous materials, but we have learned how to handle them. It has Dr. Louis Schwartz (Medical Director, been a very great experience for us and for Dermatoses Investigations, United States myself, and again the best teacher. Public Health Service, New York, N. Y.): I am primarily interested in dermatitis and 1 Db. Cecil K. Deinker: Can you recol it was only because of my researches in that lect the air concentration that you are main field that I happened to come across infor taining now with your present ventilating mation given to me by Dr. Gray that there equipment? were some cases of yellow atrophy of the liver attributed to halowax. I can only Mr. F. R. Kaiuer: We have had two talk from personal experience about the skin examinations made of the air by Mr. Wil cases. I know_from what I have seen and liam F. Hemperly and they average from 0.2 from what I have heard from doctors who to 0.6 mgm. per cu. m. We recently dis have been treating these cases that if they covered one condition which was found as are treated like an ordinary acne vulgaris the cause Of a high reading in one of the and kept away from further large exposure examinations. The compound is one that they alhgct well, with the same results as is not manufactured by the Halowax Cor acne vulgaris. Those who have large pus poration that is used rather infrequently, tules may have scars resulting and those perhaps not more than 50 gallons of it in a who have superficial pustules or only come 6 month period. It is in the form of a paste, reduced with solvent to a paste form, and it was not known that it contained a chlorin ated solvent in certain percentage. We dis covered it only recently through the analy sis of a sample and we found that that was the cause of throwing the results off to a high value. It was then about S mgm. per cu. m., I believe. That is going to be eliminated now. That is a combination of toluene and carbon tetrachloride solvent. When that compound is exposed to the air the chlorin ated Eolvent odor is completely masked by the toluene. It is lost. I was able to detect it only by removing the head of the drum and immediately smelling the odor of carbon tetrachloride. As soon as that head was removed for a period of 10 seconds the tolu ene predominated and we had no knowledge of the other being in there. dones won't have any scars. As far as prevention goes, I felt even be fore this investigation was undertaken that this substance, like any other poisonous substance, can be haudled and used in in dustry provided proper safety precautions are taken, and I so advocated at the meeting in Pennsylvania when this was discussed. About ventilation and safety precau tions, I think that while we cannot, with our present knowledge, detect by any chemical tests the early symptoms of intoxication from this substance, the skin oflcrs an easy way of proving whether your method of ventilation is efficient or not. If there are any cases of acne or of this dermatitis occur ring in a plant where halowax or the chlorin ated naphthalene or chlorinated diphenyls are used, then that shows that there is suf ficient concentration of these substances in the air to cause plugging of the follicles and Mb. Arthur G. Beteb (Research Engi to cause a skin condition. If there is suffi neer, United American Bosch Corporation, cient concentration to do that there may be ^I :* : yyrr rr; .... . ; 0s\l\f 346109 t 1I STLCOPCB4084428 3* 1 sol.19, no. 7] EFFECTS OF CHLORINATED HYDROCARBONS 305 I I sufficient concentration to cause systemic - Mr, Warren A. Cook: I am not quite, poisoning in the few people who are hyper* sure that I have in mind exactly what you sensitive to the action of these hydrocar want in that regard. In connection with bons. Everybody is not hypersensitive to sampling? , '' them. If they were, of the thousands of people who have been handling these sub Dr. Cecil E. Drinker: Yes, In con stances, more would have contracted this nection with the whole technic of determin disease and it would have been reported ing the material in air, length of sampling, very much earlier. This material was used type of apparatus, and so forth. It has in Germany as early as 1914 or 1915. been suggested that we endeavor to agree While I cannot add anything to the upon some uniform procedure for that and methods outlined here for safety in the way' as figures begin to come in, as they will in of ventilation and so forth, I can say that the course of the next couple of years, we I i if you go into a plant and find that there is any acne present among the workers with this material you will know that there is sufficient of the substance in the air to cause will at least have them on a comparable basis. - Mr. Warren A. Cook: In that regard t fthic. acne and consequently sufficient perhaps to there is no question but what the determina \ be dangerous to the few people who are tions and results of analyses of the concen hypersensitive to its action. tration of injurious materials in air, corre i Dr. Cecil K. Dp.ixker: There is a prac lated with pathological findings or freedom tical point in regard to the question of deter from pathological findings, are real factors I mining these substances in air. My brother in further substantiating toxic limits which pointed out this morning that there are are originally given us from animal experi several pieces of apparatus for doing this. mentation. In order to obtain data which It has seemed desirable to a number of the are of value alongihat line it is desirable to men who are here that during the next cou know to what ext ent, in terms of milligrams ple of years, while we are in a position of per cubic meter, workers are exposed to learning, that we endeavor, if we can, to in breathing any potentially injurious confine our analyses to one piece of appa material. ratus, so that at least our results will be as It seems to me that one of the things that comparable as we can make them from place should be done, which many of the plnnts to place. and many of the organizations equipped to I don't know much about this phase of make determinations of injurious materials the subject: perhaps, Mr. Cook, you have in air should do, is to make an eilort to an idea or two about that. develop one group and scries of results which will represent average exposures of Mr. Warren A. Cook (Chief Industrial workers to chlorinated naphthalenes. In Hygienist, Bureau of Occupational Dis getting that figure I think that it is of great eases, State of Connecticut Department of importance that wc should consider average Health, Hartford, Conn.). On the deter daily exposure. There is a tendency very mination of the halowax I wonder if it often in taking samples of air to determine wouldn't be preferable to have Mr. Hem- maximum exposures, to get the exposure perly discuss the method he has been using over a 15 or 20 minute period when the throughout the country for the determina worker may be actually tending a pot where i tion of chlorinated naphthalenes. the material is being used, whereas during the subsequent half hour he may be 40 or Dr. Cecil K. Drinker: I think so far 50 feet away from that particular location. as that is concerned it is best to leave that Therefore, for one thing, it secins to me it to discussions with Mr. Hcmpcrly and Dr. would be extremely desirable to obtain in Brandt afterward. But the question of formation in as many plants and as many determining some uniformity of technic for locations as possible of the average expo a while at least is, I think, a matter of gen sure, taking into consideration not only the eral interest to us. worker's maximum exposure while actually DSW 346110 STLCOPCB4084429  i' "Mi j 'i -; -J 'i -:= V '! 1 : . .. - Jy3frani-. -a*.Av. -jv^-.-Xa 306 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY ISept. 1937 at work with these materials but also his much smaller exposure and possibly even lack of exposure as he may go to other parts of the room or even to other departments during the course of the day. Another type of determination which seems to be extremely desirable to have is concentrations of the chlorinated naph thalenes at certain reference points. I believe that Mr. Hemperly very carefully duplicated these reference points in each of the plants where he took his determina tions. He took the samples, I believe, at breathing level and a certain measured dis tance from the pots where the chlorinated naphthalenes were being handled, so that next year he could go back to those same locations or others could take determina tions at those same locations, which are definitely fixed and recorded, and learn whether, due perhaps to clogged pipe lines or to fans which might become loaded with the condensed chlorinated naphthalene, there might be poorer ventilation than origi nally designed and higher concentrations of the chlorinated naphthalene than origi nally determined. It seems to me that it would be an ex tremely desirable thing to have made avail able for all of us who are making these determinations these reference points so that in Massachusetts and in Connecticut, at one plant or at another, a considerable group of workers could be taking samples at this one particular point with reference to the source of generation of the vapor. Such results would permit a comparison of knowl edge between plants. In that regard it happens that there is a committee of the American Public Health Association which is charged with the devel opment of chemical methods for determina tion of atmospheric contamination such as that now under consideration. It seems to me that it might be a very desirable project for that committee to consult with the in vestigator of the Halowax Corporation and suggest to all of those who are doing work of this type, after some discussion, what reference points could be adopted and also what should be done in connection with get ting these average exposures. As a matter of fact our committee will discuss that very feature and possibly include it in our report before the A. P. H.'A. in October as one of the projects which we shall carry out at -that time. As I have not given this consideration, I am afraid my discussion is not as connected as I might wish it to be. We have a real problem bere and one that deserves some 6tudy. " Dr. Cecil K. Drinker: Would it be of service to the American Public Healt h Asso' ciation Committee if a sub-committee from this meeting, collected perhaps by my brother and those of you involved with these problems, were to make a recommendation to the A. P. H. A. as to the things you have brought up and as to suitable apparatus, and let the final statement come from the Association after they have considered that material? Mr. Warren A. Cook: I think that would be a splendid idea because we have a bulk of information on this particular material. A number of individuals have given much thought to the development of apparatus, both the combustion method which we have here and also the continuous record type of apparatus which Professor Drinker mentioned this morning. I think that it is a sufficiently important project that a sub-committee made up from this group could give that committee a very definite steer. ~ [Personnel of the Sub-committce: W. A. Cook, chairman, A. L. Coleman, H. B. El kins, W. B. Fulton, S. W. Gurney, E. R. Hay hurst, W. F. Hemperly, F. W. Sehl, and A. N. Setterlind.J Mr. Hervet B. Elkins (Chemist, Divi sion of Occupational Hygiene, Massachu setts State Department of Labor and Indus tries, Boston, Mass.): In connection with what Dr. Schwartz has said, I am not sure that I am in complete agreement as regards the use of skin lesions as warning agents. It is my understanding that in insulated wire plants the chlorinated diphenyls are very commonly compounded with the chlo rinated naphthalenes. It is also my under standing that these are more likely to cause a severe skin irritation than the straight chlorinated naphthalenes. On the other DSW 346111 pj.uw.1. STLCOPCB4084430 wd.19, no. 7] EFFECTS OF CHLORINATED HYDROCARBONS 307 hand, from Dr. Drinker's work one would to attempt to get the concentrations low. : judge that the straight chlorinated naph- We saw this morriirig that the effect of these thalcnc v.as nearly as toxic at least as the products was on the liver and that if some mixture of it with a 6mall amount of chlo one working in these products developed rinated diphenyl. - liver damage from some other source the In the condenser factory where we had chances of his haying serious trouble was our cases there is no chlorinated diphenyl increased. Therefore, inasmuch as there is used and no acne of the type described in ; no test to tell whether a person has had liver the reports on the insulated wire factories. disease, certainly in the preliminary medical examination of applicants for work the his Dk. R. Emmett Kelly (Monsanto Chem tory at least should be gone into very care ical Co., St. Louis, Mo.): I can't contribute fully for a history of previous liver diseases. anything to the laboratory studies but there There are other things that should be has been quite a littlc'human experimenta taken Irilo consideration also. One is the tion in the last several years, especially at history of syphilis, because syphilis does our plants where we have been manufactur have an effect on the liver. If there is any ing this chlorinated diphenyl. It has been history of syphilis I don't think that that our observation that although on one occa man should be hired. A Kahn test should sion we did have a more or less extensive be taken and I think that it would be a good series-of skin eruptions which we were never plan to take Kahn tests on men at stated able to attribute as to cause, whether it was intervals, because they might develop impurity in the benzene we were using or to syphilis after they are hired. the chlorinated diphenyl, we have never had I think those things should be done even any systemic reactions at all in our men. though we feel that if the concentration of We have examined them very closely both these vapors in the air is kept as low as was from what laboratory tests we thought recommended this morning, the chances of might heip us arid from the clinical view having toxic effects are very small. point. Also from chlorinated diphenyl alone there have been no cases of systemic Mb. F. R. Kaimer: I would like to clarify poisoning reported. a point of Dr. Hookey's. I don't believe that we can transpose the You mentioned at the beginning of your laboratory results into the actual humans talk that your experience in acne condition without paying considerable attention to was more pronounced from the compounds the volatility of different substances and the of various materials with chloronaphthalene way they are being used. than with the straight chloronaphthalencs. Did you mean by that, that the acne condi Dr. John A. Hookey (Consulting Der tion actually was more pronounced with the matologist, Ilalowax Corporation, Detroit, compounds than with the straight chloro Mich.): I have had considerable experience naphthalene or was that due to the fact that with the dermatological angle of this prob you were in a plant operated in a different lem. The experience at the Halowax plant fashion? In other words, you handled your at Wyandotte definitely wns that the derma numerous wire compounds in more of a tosis did increase when compounds were batch operation. That is my understand used rather.than the straight chlorinated ing from Mr. Brown. naphthalenes. Is it a fact that the straight chloronaph- From the discussion we have heard today thalcncs are less harmful in so far as acne I think the observation Dr. Drinker made is concerned or is it because of the handling that the chances are that dermatological of batch compounds? problems will disappear along with the other is probably true. However, I think that Dr. John A. Hookey: That is a question certain precautions, certain insurance meas that would be difficult to answer. I based ures, you might say, should be taken in my statement on the fact that in taking a . hiring men who are going to work with general survey of these cases after I started these products, even though w'e are going working with them the men in the plant said r* i > r s : ! t I t- i i : . V DSW 346112 'm STLCOPCB4084431 diitmis+h t 308 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY ISept. 1957 - *i that they developed acne more often and vulgaris is most apt to occur. The seltacemore severely after they started making ous glands are most active and they seem to compounds. It may be that it was in the :|SfSpsSw method of the handling. have it much more than the older people in whom the sebaceous glands are not so ' - = -v; Mb. F. R. Kaimer: You say that the con dition increases with the increased chlorine content and we are attributing the acne pri marily to the chlorine radical. If that is true, what are we to associate insofar as these various other constituents are con cerned, such as various plasticizing agents? How much do we know about those insofar active. We keep a clipping of all articles relating to industrial dermatitis in my office and I recently read an article in a German maga zine in which they report in Germany a similar acne condition from chlorinated phenols and chlorinated benzenes and solid waxes. It seems that this acne-like condi tion is not peculiar to halowax or chlorin as development of acne is concerned? Some ated naphthalenes or diphenyls but can of these compounds have a half dozen con occur with any condition that blocks up the stituents in them other than chlorodiphenyl sebaceous follicles of the skin. and chloronaphthalene. VTe are at the Z-. present time considering the chloronaph Dr. Rotav/Meeker (Special Agent, thalene as the basic element responsible for State of Connecticut Department of Labor, the acne condition which we have. We Hartford, Conn.): I am full of questions. know very little about what the other mate As ft statistician I am a little bit suspicious rials may or may not do. of averages, so I should think that we should take maxima as well as averages in getting Dn. John A. Hooket: I don't know at the threshold dose or llie'dangerous im z about these other materials. Perhaps Dr. pregnation of the atmosphere with these Schwartz weald know something more poisonous compounds. I just wanted to "v about them. drop tbat as a hint for this committee to consider in its work. Dr. Louis Schwartz: It is well known In spite of what you said at luncheon, in industry that there arc many compounds Dr. Drinker, I still think it is rather impor that cause acne. For instance, paraffin tant to determine how the plugging of the acnes and oil acnes have been known for a pores actually does'occur, whether they are long time. Paraffin acnes, wax acnes, are plugged as Dr. Schwartz has suggested, simply s mechanical plugging of the fol from the particles falling on the outside of licles of the skin by the minute particles of wax that fall on the skin. I think that the acne caused by these chlorinated naph thalenes and diphenyls, because it is caused by both--I was down at the Swan Chemical the skin or whether they stc plugged, as so many doctors have informed me, from inside as it were. The fumes are breathed, the substance gets into the blood stream- It is thrown off through the pores of the skin and a t j I ; j Company where they make chlorinated di phenyls and they have acne there just the same as over at Wyandotte where they make the chlorinated naphthalenes--I believe that that is caused by the same thing, a blocking up of the follicles of the skin, the formation of the comcdone and tlien the comedone becomes infected Rnd forms a pustule. They don't all pustulate because the pores are plugged. I think it is rather important to determine that because it seems to me, from the slight knowledge that I have of the industrial application of halowax compounds in insulating wires, that the plugging of the skin, if it is just an out side plugging, may take place either from handling a solid substance or from the coating on the wire after it becomes cold. they don't all become infected. Many of 1 haven't heard anybody say anything these men never have any pustules. They about those Massachusetts cases of very just have little white elevations on their skin. In those people who are in the acne age, the youngsters of 18, 20, 22 and 23, sene severe dermatitis and I nm not so sure but what there was some question of liver dam age there. Nobody has said anythingabout them at all. There is no question there sol the tio col 3 Dr ha' cui the bot 3 < ex\ cat &n< lef wh po to be pic Mi Co it. sat ell all rat cat or un rat Ge Co ve; he' bein of tui fat be: *ei vc flli Co: in: to ou eb wt ae< A DSW 346113 J--. \ STLCOPCB4084432 -4 .. ,, Cm! l; -i--' .y- .- - ii... - -HI -LJOii**-. wf. IS, no. 7] EFFECTS OF CHLORINATED HYDROCARBONS 309 that the condition, whatever the complica tions might have been, came from handling cold wire, in a confined area of coarse. ` I think this needs a great deal more study. Dr. Drinker, than you and your associates v have been able to give it as yet. All I am curious about is the way we can administer the protective labor laws in order to protect both the employer and the employee. ' I listened with very great interest to the expositions of suggested pots for the appli cation of halowax, chlorinated naphthalene and diphenyl. It seemed to me that they left very much to be desired. I don't see why the application of the halowax com pound, if it is necessary, as I assume it is, to use this rather dangerous substance, can't be done in a practically closed pot. If you please. Dr. Drinker, I wish you would ask Mr. Reeves of the Rockbestos Products Corporation to tell how they have handled it. If I am any judge of equipment and safety devices they have come as near to eliminating entirely from the atmosphere all contaminatiou from fumigated or evapo rated halowax as anyone. All of the appli cation of halowax, either in the melting pots or where it is applied to the wire. j done under hooding and with ventilating appa ratus, and it seems to be entirely adequate. wax we bad a head start as far as tbe ventilating system was concerned, since ours was already installed and adaptable to a compound with a benzene solvent rather than amclted halowax compound. In order to keep the fumes of a highly volatile sol vent under control we did develop a prac tically complete enclosure for the container in. which the compound was placed and exhausted that container in order to prevent any escape of the fumes from it. When we changed to the halowax compounds we fol lowed the same scheme of applying the compounds and used a completely enclosed pot. There is a hole in one side for the wire to go in and one on the other side for the wire to come out. There is enough exhaust suction on the enclosure to prevent any fumes from getting out of the openings where the wire enters and leaves. Of course periodically it is necessary to open the pot to replenish the compound or make adjust ments. In that case we have the ventilat ing system interlocked with the door that the operator opens so that when he opens it he increases the amount of air travel about ten-fold. ,. Dr. Royal Meexer: What is the veloc ity when the door is open? . Mr. B. H, Reeves (Vice-president and General Manager, Rockbestos Products Corporation, Xcw-Haven, Conn-.): I will be very glad to tell of our experience if it will help the picture along. Our experience has been more or less parallel with Mr. Kaimer'a in as much as we manufacture the same type of wire. We have avoided the serious pic ture that he ran into, probably due to the fact that shortly after 1923 we were using benzene as a solvent for asphaltic materials. We got into anemia difficulties with ben zene fumes and had to install a complete ventilating system to remove all those fumes from the machines that applied the compounds to the wire. Following the installation of that equipment we were able to get a substitute for benzene, so we got it out of the picture. We are still in the same fix as every one else is as far ns finding a substitute for halo wax. There is none that we know of. Con sequently when we went to the use of halo- Mb. B. H. Reeves: With the door wide open, at breathing level the velocity is 200 feet. That is the' linear velocity. We check that every week on every opening at every machine with a velometer, a small instrument which is easy enough to operate and reads directly. Whenever the velocity falls below that figure the pipe connecting that machine is taken down and cleaned, because there will be condensation inside the pipe to cut down the air flow and reduce the ventilation efficiency. Dr. Royal Meeker: What do you think of that trap device shown7 Mb. B. H. Reeves: I don't know what to think of that. I don't know' whether it would be practical or not. I was going to ask Dr. Drinker whether in passing the air laden with hulowax fumes through the boxes of rats there was any deposit of halowax in the enclosure. . L l l l i i f f i 05^346114 STLCOPCB4084433 uiiui 310 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY (Sept. 1057 Dr. Cecil K. Drinker: Yes. It is complaints were bona fide. We had no dif detectable readily through the outflow pipe. ficulty in handling cold wire and the men . had no skin trouble. Yet when `they did Mr. B. H. Reeves: Those in the far end the same thing with possibly the application probably didn't get the concentration. ~ of heat in tunnels, 6hips and so forth,'they actually did develop trouble. Dr. Cecil K. Drinker: We change the We have used, of course, the icterus index position of the boxes each day. The ones in following some carbon tetrachloride cases furthest away move into the nearest posi and I wondered what you have to say about tion, so that over a period of weeks all are . that. Is that of no value at all in the case exposed equally. of liver damage in this material? 3 Dr. Emert R. Hathcrst (Consultant Dr. Cecil K. Drinker: I don't think so in Industrial Hygiene, State Department of until it gets so extreme that we know it any Health, Columbus, Ohio): I would like to way. ' ; ' ' 7-' - ask if it wouldn't be possible to put a cold water line around that trap and deposit it Dr. B. L. Vosburgh: I did write down a 1 all before the air escapes from the trap. few questions that came to mind. Some of them have been answered and some are Mr. B. H.Reeves: We have tried cool foolish but I shall ask them anyhow. -- ing the surface of the exhaust pipes in order It occurred to me that if trichlornaph- to concentrate the deposit in one. place and thalcne has been proved to he practically make it unnecessary to remove long lengths innocuous, isn't it a problem of research of the ventilating system. While we have largely' for the Halowax Corporation to use found a slight advantage in doing so it only that one material adopted with other hasn't at all paid for the expense. It is known chlorinated compounds to meet the much easier to take the piping down. Con requirements of customers? That is one sequently I doubt the possibility-of remov of the foolish ones probably, but I shall ing it all by cooling the surfaces of the trap. just ask it. " 7 It might be possible, by building a labyrinth Furthermore, how long is it reasonable to of refrigerating coils, to collect it. But expect the liver to recover after it has been then you would have the problem of remov pretty well damaged. I talked to you and ing it from the coils after you Lad collected you said you hadn't worked that out with it and it would involve rather complicated the animals as yet. procedure. -- - Dr. Cecil R. Drinker: In that case we < Dr. B. L. Vosburgh (Medical Director, set aside a certain number of animals to General Electric Company, Schenectady, recover, after knowing that a certain New York): Wc have heard about the pos amount of damage had been done. Then sibility of preventing liver damage and skin wc started to kill them but we invariably trouble among manufacturers of wires and ran out of rats before they ran out of lesions. 1 cables and so forth, hut like the old rhyme, Wc don't know' how long it lasts. every dog has fleas and the fleas have fleas, wc also have customers who use wires and Dn. B. L. VosBURcn: Have you given cables in tunnels, in enclosed spaces, splic them calcium and glucose as you would with ing them together and doing all sorts of carbon tetrachloride? things. I am not at all certain that we know "i what the concentration of these chlorinated Dr. Cecil K. Drinker: Not yet, hut we i hydrocarbons is under those conditions. are doing an experiment now with one group About the time wc were having so much on a very high calcium diet and another trouble at our York factory some of our group on a calcium free diet. The whole customers began complaining. We thought question of calcium in the diet, of giving i we were having a hysteria of halowax mania milk daily to these people may be worth throughout the country. Some of their while. : wf. r que: wha bilil chic h aim] froi the I tl too the . Th( ind chl< r. J trhi OUT Ifil; Dn der COE son ire ren uet am a it abl on< vii the SOI COJ qu tin mI to so th or al 1 *.-*L V'liJM1 STLCOPCB4084434 vol. 19, no. 7] EFFECTS OF CHLORINATED HYDROCARBONS 311 Dr. B. L. Vosbtjrgh: 1 just had those syphilis during the time they are working questions in mind. I would like to hear for you, you are probably going to lose some what Mr. Brown would say as to the possi ; very important employees. It would seem bility of using only this one innocuous that it would be worth while to give serious chlorinated naphthalene. consideration to seeing that conditions are proper and suitable for them to continue Mr. Sandford Brown: That would .,: working for you and that they have proper simplify our problem exceedingly, not only treatment. In other words, I don't believe from the commercial standpoint but from that is a good or sufficient reason for dis the toxicity standpoint. But if vc did so charging those employees who do develop I think that Mr. Kaiincr would be the first syphilis. We have not found that to be to object because he wouldn't be able to get true in other places and I question whether the technical effects he desires in the cable. this is one of the places. I may be in error. The same thing applies throughout all the industry where we are using these higher Mr. Sandford Brown: I want to take chlorinated products. this occasion to express on behalf of the The problem as we see it, and it is one Halowax Corporation my thanks for the which we intend to study further (we have excellent cooperation we have received from our program for this continuous work that various state authorities and our customers will be done under the direction of the as well in this investigation. 1 believe you Drinker brothers), is to try to find a line of ' have all formed the opinion, based on what demarcation and whether or not within this you have heard this morning, that our whole complicated chemical structure there is motive here is to conduct this on an ethical, some one thing that causes the trouble. If scientific and constructive basis. we could take hexachlornaphthalene and In collaboration with the Monsanto remove 1 per cent of some unknown constit Chemical Company we have a much more t uent with .which wc are not now familiar comprehensive program in view to carry on. I 1 and eliminate the tcxic:iv, that would be a lovely solution. Whether wc will ever be able to attain that I don't know. That is Therefore wc want to continue that same type of cooperation. There is one tiling that I want to bring up one of the thilgs we have in mind. in that connection, which will have to be As I said before, that is one of the things observed by the state authorities, when they with which all manufacturers of these syn go out to make these inspections. That is thetic organic products are confronted at the necessity of not creating mob hysteria some stage, cither in their laboratories or in on the part of the workmen in the plants commercial developments. It is largely a where these insjicctions are made. Mr. question of timing as to when you should do Hcmperly has run into some very interest the work, how much you should do, and ing situations in the various examinations whether you know how to do it. You have he has made. I know that he would be glad to learn that first. to relate them and give the benefit of his experience to the heads of any of these state Dr. Cecil K. Drinker: Unless there is some other important matter I will declare the meeting adjourned. departments who will have the direction of this work. Otherwise I can see where wc will be unable to get the full cooperation of not only the individual workmen but the plant foremen and the management, and we Dr. R. R. Savers: May I say a word must have that if wc arc to get the results more with regard to what Dr. Hookey stated that we are shooting for over the next sev on syphilis? If you arc going to eliminate eral months or years. This thing may con all your workers who happen to develop tinue, probably will continue for years. c r r * t [- STLCOPCB4084435