Document mq47bDRVyO6OKz05VnEk3n2X0

THE JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY Volume 19 SEPTEMBER, 1937 Number 7 THE PROBLEM OF POSSIBLE SYSTEMIC EFFECTS FROM CERTAIN CHLORINATED HYDROCARBONS* Cecil K, Drinker, Madeleine Field Warren and Granville A, Bennett Department of Physiology, Harvard School of Public Health and Department of Pathology, Harvard Medical School, Boston, Mass. HE use of chlorinated naphtha Tlenes and compounds of allied pharmacological possibilities is extremely wide, and with the steady growth of the use of electricity is cer rapidly and thoroughly as possible.! In brief these cases were as follows; Patient t. Male, age 21, The previous medical history of this man was in no way significant except for the fact that he had 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 an attack of jaundice about 6 weeks prior to his fatal illness. I,ate in December, 1938, lie 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 investigations have not been concerned with chloracne but with the possibility of systemic effects following ingestion or inhalation of such products. In the 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 spring of 1930, the Halowax Corpora tion, a division of the Bakeiite 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 for publication June 30, 1937. 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 "halow&xes1' by purchasers and users, and are lumped 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. 284 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. IBS7 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 pentachlornaphthalenes, together with approximately 10 per cent of a refined chlo who had been exposed to trichlornaphthalene. Of these 13 were found to have mild digestive complaints, anorexia, nausea and vertigo, but Courtois-Suffit remarks finally, "Ab rinated diphenyl. While both he and other* 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 a* treatment with artphenamme sorption 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 or exposure to dangerous concentrations of carbon tetrachloride. Palteni I. This was a young man who died in February, 1936, after an acute illness characterized by jaundice. Ho had been exposed to fumes arising from a mixture of the mildness of the digestive troubles and the absence of respiratory phe nomena." In Tourainc's cases the exposure was to a trichlornaphthalene, whereas the penta and hcx&chlornaphthalenes. 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. American cases of acute yellow atrophy were exposed to compounds of higher chlorination, Our own experiments indicate that trichlomaph thalenes re Patient 3. 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 yellow atrophy of the liver Here again no history could be ob quire enormous dosage, far beyond anything encountered in industry, in order to produce liver damage. Teleky (1927) reported a number of cases of chloracne in persons exposed to tained as to a precipitating cause, and there was no record of preceding attacks of jaundice. chlorinated naphthalenes with a chlo rine content ranging from 14 to 53 per cent. He found that the lower the In addition to those three very re chlorine content the less the acne. cent fatalities, tve have learned of four Mittelst&dt (1935) examined a number other possible cases, none of them of cases of chloracne due to trichlor fatal. All of these have had jaundice naphthalene and reported a number of and the entire group consists of iso vague general complaints but nothing lated individuals who have been picked in the nature of serious disease. Re out of large groups having the same garding his animal experimentation, exposure. In hut one instance, Pa Lehmann (1919) reported that ani tient 1, is there record of antecedent mals fed chlorinated naphthalenes re disturbance of health, and the general fused to eat after a time and that, health of fellow workers has been good. whether poisoned by inhalation or by Such cases have not been reported feeding, at death showed "peculiar" in the medical literature and only occa lesions in the liver. Flinn and Jarvik sionally can one find reference to sys (1936) gave subcutaneous injections of temic effects of any sort. For exam enormous doses of chlorinated naph ple, Courtois-Suffit (1934) reports on thalenes dissolved in paraffin oil to work done by Touraine and his asso rabbits. The compounds used were ciates (1934) who examined 60 workers as follows: TOXSTUDIES0006 not. 13, no, ?l EFFECTS OF CHLOIUXATHD HYDHCK'ARBON'S 288 1. A mixture of tri and tetrachlornaphthalene, 2. A mixture of tetriv and pentaehfonmphthulene, 3. A mixture of pcnta ami hexachlurnaph thalcne. In addition, sublimates from (2) and (3) were collected in oil and injected subcutaneously. None of the animals receiving (l) or the sublimate from (2) died, and oven 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 20th day, Those receiving the sublimate from (3) wen* even more severely n fleeted. 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 paper, Fliirn and Jarvik (1930) 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. One may summarize the meagre literature tqxm systemic effects from these substances as follows; 1, With the exception of the men tion of acute yellow atrophy by Flint! and Jarvik (133t>) there arc no reports or even suggestions of serious effects upon human beings, 2. There is evidence (Telekv, 1927) that the degree of chlorination is sig nificant in relation to the production of acne. In the work of Finns and Jarvik (193<i) tin1 compounds produc ing serious liver injury were the most highly chlorinated of those tested, though tin* chlorine contents as given by analysis vary surprisingly little. 3. There are no published figures Ujxm 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 Flitm and Jarvik (1930) point tn the liver as a possible site of injury this indication rests upon such extreme dosage us to fail to apply directly to human exposure, Hxpkiuxiu.vtai. Wohk In appraising the possible toxicity of any substance met in industry it is first necessary to determine the prin cipal route of absorption. In the case of the compounds under consideration there run be no doubt that tiihalatiun is their chief means of entering tin* body. They arc 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 tin* air under such circumstances are hardly detectable. It will however be shown that carbon tetrachloride adds to the toxicity of the chlorinated naphthalenes and allied compounds, atul if there is possibility of inhaling these compounds in other parts of the factory then inhalation of carbon 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 286 .lOl'RXAL OF IMH'STIUAt. HYGIKXK AXD TOXICOLOGY \Sepl. 1837 workmen may lie extremely dirty and careless, comparatively little of these waxes is eaten. They are tenacious substances, insoluble in water, ami if they get on the hands they stick there and are not transferred to the food. Skin absorption is the third possible means of entering the body. It- may occur but at best must be slight when compared to the steady inhalation of finely divided or gaseous material in the air. Hon. They thrive upon a diet very similar to man, and in the ease of these chlorinated compounds it is possible that diet may be very significant. Finally, their normal characteristics have been described so well as to make the detection of abnormalities both easy and certain. Method of exposure,--The inhalation experiments were carried out in four large air-tight wooden boxes, each capable of holding ten rat cages, size Fm. 1. Front view and inflow end of two boxes with rat cage* in place and doors open. Inhalation experiments arc then the most important sources of information, but to them wo have added a certain number of observations tt)am ingestion and subcutaneous injection of various compounds. Inhalation Experiments A nrinnlr.--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 experiment was not in progress the doors were opened wide and the cages kept in place (figure 1). At the center of one end of each box --the inflow end--air was introduced through a pipe 7 inches in diameter (figure 2). Mach box was equipped with an individual variable-speed elec tric blower which blow the air through .several feet, of 7-inch pipe before enter- vnl. 19, ntt, 7| KFFIXTS OF Olll.OlUXATKD HYDHUCAHHONS 2S7 ing the end of the bos. An orifice meter was platted in the pipe line, and the flow of air in euhie 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 bos the out How end (lie air from each bos was exhausted through a 7-inch pipe fitted with a damper and eonoeeied to a large central exhaust fan tfigure di. .About 4 inches from the entrance of the 7-ineh pipe into the box, the fumes of the substances listed were intro duced into the inflowing air. Spe cially designed pvrex glass Masks (figure 4), 7f inches long and with a diameter of U inches, were used to hold the heated waxes. These flasks were made with a side arm ami tube that extended to the bottom. The top of the Mask was ground, and into this fitted a short tube 1'. inches in length. This short tube was inserted into a large rubber stopper that fitted tightly into a hole cut out of the 7-iucli pipe on the under side (figure 2). Tinflask in turn was placed in an electric heater made to rover it completely below the side arm and ground gIns top, Httbber 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 n long stem centigrade thermometer which was kept in place anti could be rent! at any time above the 7-ineh 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 Mask 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 ease, the collected sublimate was Fjii. 2. KU-rtriu beater for nmiutauiing chlorinated campmimia at a constant tem perature in place at inflow end of box, always removed from the tipper partof 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 FV;. 4. Pyrox flowmeter readings. The figures ob tained were not absolute because of slight variations in the air flowing through the boxes ami because of deposition oi material on the ther mometers am! on the inside surfaces of the box, but they cheeked well with direct determinations through air samples. Approximately i hour was allowed ir I lie wax in t he flasks to melt, and come In a constant tempera!life. At that time the box doors were tightly is4`d, air bubbled I hrottgli the flasks, and the blowers turned on. This was the beginning of the exposure period. By means of rheostats on the fans and dampers in the outflow pipes, tin* amount of air flowing through the boxes was adjusted and ait attempt Wits made to keep the four boxes as uniform as possible--usually between 105 and 175 c.f.tn. In the first group of experiments the following substances were tested; 1, A mixture of Uichiornaphthalenesplusa trace of tetrachlornapthalene. Chlorine content 49.9 per cent. A mixture of penta and hexaehlonmphthrdene*. Chlorine content 62.0 per cent. A mixture of 90 per cent penta and hexachlornaphthalcncsj plus 10 per cent refined chlorin ated diphenyl. Chlorine con tent 63.0 per cent. Chlorinated diphenyl. Chlorine content 65.0 per cent. The compounds were selected as rep resenting a certain range in chlorina tion and also because of their industrial importance. In each instance 80 ani mals were exposed, 10 rats being placed in each cage. They were fed Purina TOXSTUDIES0010 l. IS, no. 7] EFFECTS OF CHLORINATED HYDROCARBONS 289 Dog Chow supplemented by lettuce, eggs, milk and cod liver oil. This first group of experiments was begun on July 1, 1936 and the last exposure to number 2 (penta and hexachlornaphthalen es) was on November 16th. The exposure to the other three compounds ceased upon November 18th. On October 15th representa tive animals were taken out of expo sure from groups 1, 2, and 4 and were killed after 2 months on December 15th, in order to see whether this clear wax concentrations were somewhat higher at the inflow end of the boxes. Preliminary runs showed that once properly adjusted, wax concentrations in the air remained very uniform from day to day, but to insure absolute safety readings of temperature, air flow, etc. were made every night be tween 10:00 and 12:00 p.m. as well as on starting and stopping. At dif ferent times during the course of the experiment tests for free chloride were made but were uniformly negative and TABLE 1 Conditions Maintained in Inhalation Experiment from July 1 to November 16 and 18 MATERIAL CHLO coRHINTEtirr TSM*. or INAY, CONCX.KTKATION AIR BOX TOTAL roECXR- AV, BAIL* E3C- POBCRE % *c. m. ran** haunt Aeurt TrichlornaphtbaleneB plus traces of tetrachlornaphthalene................... 40.9 150-160 1 31 High 2 .60 1896 16 Low 0.10 Penta and hexachlornaphthalene*.... 62.6 160-170 1.16 High 2.19 1864 Low 0.51 16 00% penta and hexaehlomaphthaienes plus 10% chlorinated diphenyl. 63.0 165-175 1 37 High 3.17 Low 0.64 1896 16 Chlorinated diphenyl.......................................... 65.0 165-175 Q ,67 High 1.19 Low 0.23 1896 16 period would bring about recovery in the affected livers. Animals from group 3 were similarly removed from exposure on October 4th and killed for examination on December 4th. The average length of exposure was 16 hours daily for 6 days a week. Each morning at about 9:00 exposure ceased, and between this time and 4:00 p.m. the rats were cleaned, fed, weighed, etc. In order to secure uni formity of exposure the cages were shifted on a regular schedule, since showed that under the temperatures used no decomposition occurred. Table 1 shows the temperatures at which the various substances were held, the average concentrations per cubic meter of air, and the average exposures from July 1 to November 10 and 18. The concentration of chlorinated naph thalenes and chlorinated diphenyl in the air af workrooms.--Table 1 shows that animals have been exposed to varied concentrations of the substances under 290 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sepl. I8S7 test. The concentrations employed may be regarded as fairly representa tive of industrial experience. Prior to the initiation of inhalation experi ments a number of estimates of chlo rinated hydrocarbons in the air of dif ferent factories were made arid the sucnoN in question is passed over heated plati num in an electrically heated quartz tube and the effluent gas scrubbed in a column of glass beads moistened with sodium carbonate containing a trace of sodium sulfite. The beads are then washed down and the chloride deter- 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. Hcmperiy. The method and apparatus used for determining concentrations of chlorin ated hydrocarbons in air were adapted from well-known procedures. The air mined nephelometric&Uy 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 TOXSTUDIESOOI2 ml. 19, no. f\ EFFECTS OF CHLORINATED HYDROCARBONS 291 somewhat easier to wash down than is Tebbens's but the essentials of the two devices are the same.** In both cases conversion of the chlo rinated hydrocarbons to hydrochloric acid and subsequent absorption as sodium carbonate should be complete. In our case concentrations in air are apt to be very low--the objective is less than 1 mgm. per cu. m. Conse quently the amount of silver chloride actually formed in the final reaction is so small that it can not be determined either gravimetrically or by titration. For this reason we have been forced to use the nephelometric procedure which is sensitive to concentrations as low as 0,1 mgm, per cu. m. of air. It is doubtful if the sampling rate should exceed 1 liter per minute m conversion of the chlorinated com pound to hydrochloric acid and its subsequent absorption are not efficient unless the velocity of the gas stream is tow. Another precaution to be noted is that the method is not selective-- any chlorinated substance will be determined. Furthermore it does not distinguish between solid particles and gases but determines them all alike and the results must, of course, be com puted in terms of total chlorine. At the present time we possess in formation as to the amounts of chlo rinated naphthalenes in the air of 30 different plants, and in a number of instances the measurements have been repeated several times. Frequently the amounts have been greater than those used in our experiments, but it must be remembered that the rats * The combustion and absorption appa ratus suited to field sampling is now made by Willson Products, Inc., Reading, Pa. The equipment includes flowmeter and suction pump with a carrying case. have been exposed for 10 hours to an atmosphere constantly impregnated with the substance under test, whereas human exposure is usually a variable quantity, intense for a short time and then negligible. It is our opinion at the present time that the concentra tions of chlorinated hydrocarbons used in our experiments would be dangerous for workers in the case of compounds above trichlornaphthalene in chlorina tion. Fortunately it is easy to venti late processes of manufacture which require these substances and to reduce air contamination practically to the vanishing point. Such treatment of the problem at once removes both the possibility of systemic poisoning and the annoyances that arise from eases of acne. Remits of Inhalation Experiments. 1, Animals exposed to a mixture of trichiornaphthalenes plus small amounts of tetraehlornapthalene. Living animals were apparently en tirely normal. Autopsies performed near the end of exposure seemed to show slight swelling of the liver, and microscopic examination occasionally showed swollen and hypergranular liver cells. The changes were, however, never more than slight. 2. Animals exposed to a mixture of penta and hexaehlornaphthalenes. No abnormalities were observed in the living animals. Rats were killed and autopsied every 6 weeks. In the first animals sacrificed liver changes were observed. These were swelling of cells, slight granulation and hyalinization. In September and October these conditions were somewhat more ad vanced, and in November the process became stationary. There were highly 292 JOURNAL OP INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept, 1937 granular cells, hyaline inclusions and exposed to these compounds without mitotic figures, but no more than 2 illness of any sort. months previously. 3. Animals exposed to a mixture of The functional appraisal of the liver 90 per cent penta and hexachlor- damage caused by certain chlorinated naphthalenes plus 10 per cent refined naphthalenes and by chlorinated di chlorinated diphenyl. No abnormali phenyl.--There are no testa of liver ties were seen in the living animals. function useful in such minor degrees After 6 weeks the livers showed of liver damage as were produced in changes similar to those in the animals these experiments. Indeed the ani exposed to penta and hexachlomaph- mals resisted the injury so perfectly thalenes. These advanced in grade as to display no abnormalities except during August and September and upon histological examination of the then became stationary. liver. The situation was perhaps 4. Animals exposed to chlorinated similar to that met in industry, where, diphenyl. No abnormalities were seen barring acne, the health of workers in in the living rats. After 6 weeks' ex these compounds has been good with posure there was slight liver damage the exception of the fact that in iso which advanced during the next 2 lated instances jaundice has occurred months. The changes consisted in which upon at least three occasions slight to moderate swelling of the liver has gone on to acute yellow atrophy. cells, an increased granularity and During recent years this disease has many mitotic figures. Hyalinization been seen following administration of was always present as a result of carbon tetrachloride, arsphenamine inhalation of chlorinated diphenyl. and cincophen. In the case of carbon Summary of the first inhalation ex tetrachloride it is known that a low periment.--In these experiments care calcium diet and alcohol favor the pro ful observation of appearance, body duction of liver damage. For the weight, activity, blood, and urine acute yellow atrophy that occasionally showed no abnormalities of any sort. complicates use of the other two drugs Yet after 6 weeks' exposure all the no cause can be assigned. One cannot compounds with chlorination above produce acute yellow atrophy with trichlomaphthalene caused minor de arsphenamine, but somehow or other grees of liver damage, and no changes this now and then does happen to pa- whatsoever in other organs. There tients under antisyphilitic treatment. was no acute yellow atrophy or any It occurred to us that something of thing suggesting it except that a slight the same sort might be involved in this degree of liver damage was always problem. The human cases have been present and was quite clear in the liver scattered and few. They have been sections examined microscopically. isolated instances out of large groups This damage had no detectable effect of healthy employees who have had on the health of the animals. They ' equal degrees of exposure. It was our held their weight, ate and behaved idea that perhaps many of these people normally, being in every respect similar .got liver changes such as existed in our to the many people who have been rats, changes not recognisable through TOXSTUDIESOOI4 ml. IB, no. 7} EFFECTS OF CHLORINATED HYDROCARBONS 293 any means other than autopsy exami nation. If, upon the substratum of such 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 relatively 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 cc. 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* fid 0.75 cc. per kgm. each of carbon tetrachloride and ethyl alcohol by stomach lube 1. Trichlornaphthalene plus trace of lelrachlomaphthalene. Fed at 9:00 a.m., Nov, 10,1936. 10 rats. No death*. 2. Pcnla and hexachtomaphlhalenee. Fed at 9:30 a.m., Nov. 10, 1938. 10 rate. 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. 80 per cent pmla and hezachlornaphIhalenee and 10 per cent chlorinated diphenyl. Fed at 10:00 a.m., Nov. 10, 1936. 10 rata. 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 rata. 1 killed Nov. 10th at 10:30 p.m. (almost dead). 2 died Nov. llth 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 rata. 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 trichlornaphthalene 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. 294 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. IS3T 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 arsphenamine, cincophen, butyl chloride, ethylene chloride and tetrachlorethylene, but carbon tetrachlo ride was uniformly effective in dis closing the existence of liver damage. Recovery from liver damage following removal from exposure.--Animals ex posed to trichlornaphthalenes plus traces of tetrachlornaphthalene being practically normal on removal from exposure need no consideration. In the case of the penta and hcxachlor- signs of liver injury will be many months in returning to normal. The effect of high concentrations of trichhmaphthalenes with traces of tetrachlomaphthalene.--The first group of inhalation experiments showed that this material in concentrations averag ing 1.31 mgm. per cu. m, of air was relatively innocuous, judged both by direct observation and by the carbon tetrachloride test. This is an in teresting fact since such compounds cause acne, though less potently than substances of higher chlorination. In order to explore the matter further oneof the inhalation boxes wasarranged TABLE 2 Conditions Maintained dbtuno Inhalation op High Concentrations of TniCHLORNAl'HTHALENBR I'LOB TETRACHLORNAPHTHALENE MATERIAL. TEMP, AV. ONrKWTRATIO* op aim f# box total AV, BAILT EXPOSDM XXPOSDK* Trichlornaphthalenes plus traces of tetrachlornaphthalene ns Jem. m. 137-200 10.97 ranps High 16.49 Low 5.78 Aart 1232 hovra 18 naphthalene, rats after 2 months' re moval from exposure still showed swollen liver cells, increased granu larity, hyalinization and mitotic fig ures, The condition was not advanced as compared with rats killed at the time of removal from exposure but on the other hand 2 months were insuffi cient for recovery. The same findings were true of the mixture of penta and hexarhlorinatcd naphthalenes and chlorinated diphenyl and for chlorinated diphenyl alone. Apparently the changes induced in the liver cells by these substances are exceedingly persistent and one must expect that an individual showing any so that fumes from four glass contain ers were delivered to the air line instead of one. This resulted in the conditions shown in table 2. The animals sub jected to these conditions showed no clinical effects of any sort. After 1 month the liver cells were slightly swollen and over-granular and there were occasional mitotic figures. These changes were similar to the early effects of more highly chlorinated compounds, and progressed only slightly during the third and fourth months. When rats in this condition were given carbon tetrachloride and alcohol, in some instances their livers showed massive central necrosis and t TOXSTUDIES0016 vol. IS, m. 71 EFFECTS OF CHLORINATED HYDROCARBONS 295 in others this did not develop. Fiftyrats were used in this experiment and one may conclude that while the trichlorastphthnlencs are in no degree as toxic as those of higher chlorination they are not entirely free from effects upon the liver if high enough concen trations are inhaled over long periods. The effects of high concentrations of penta and hcxachlomaphlhakrws.-- There can be no doubt as to the dam age done the liver by these compounds but in the concentrations so far re ported no symptoms were caused that could be recognized clinically and nothing approaching acute yellow the liver after 35 days of freedom from inhalation. It is thus evident that penta and hexachlornaphthalencs are markedly toxic compounds and that recovery from their effects is extremely slow. The effects of penta and hexachhrnaphthalenes, the mixture of these with 10 per cent chlorinated diphenyl, and of chlorinated diphenyl alone, when inhaled in km concentrations through an 8-hour day instead of a 16-hour day as in the first experiment,--Since steady human exposure to any of the compounds tested would invariably be for 8 hours rather than 16-hour periods, a further TABLE 3 Conditions Maintained cubing Inhalation op Hiok Concentrations op Penta and Hexachlornaphthalenes MATERIAL TJCWP, AV, eGNCCKTRATTOK OP Ain IN BOX EJCtHoOtBaVlUC AV, DAILY EXrOBGftK e. Aouv# hourt Penta and hexodilornophthaieiics........ 137-193 8.88 I High 14.0 j Low 5.73 608 16 atrophy occurred except through the use of the carbon tetrachloride test. On December 1, 1936, 80 rats were subjected to the conditions sum marized in table 3. This experment was terminated on January 21. All of the animals lost weight and appetite and deaths began after 8 days of expo sure. Fifty-five rats died, most of them heavily jaundiced, 8 were killed for microscopic examination, 9 were killed by the carbon tetrachloride 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 changes in inhalation experiment was arranged under the conditions shown in table 4 which are quite comparable to those in table 1 except for the shorter inhala tion periods. Mighty rats were used for each of the three compounds tested. None at any time showed the slightest evidence of Illness. Microscopic ex amination 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 I. The carbon tetra chloride test was uniformly fatal to them and one must conclude that con- 296 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY ISpl. 1937 centrations of these compounds such as were employed cause a certain de gree of liver damage even if inhaled for but 8 hours daily. This injury is resisted successfully by the rats just as was the 16-hour injury but it is none the less there and destroys the ability of the animal to resist the carbon tetrachloride test. Summary of inhalation experiments. The findings that have been described briefly will be amplified upon the pathological side in a further paper by Dr. G. A. Bennett. What has been given is, however, sufficient to indi men never inhale enough of any of these substances to get acute yellow atrophy. They may, however, acquire a substratum of liver damage upon which acute yellow atrophy may de velop. Experience in a number of plants has shown how easy it is to reduce concentrations of these com pounds practically to the vanishing point, and every effort should be made to attain such conditions. Gross Feeding Experiments The various compounds used were ground as finely as possible and mixed with a standard balanced ration for TABLE 4 Condition* Maintains durino Inhalation or Low Concentrations or Three Compounds durimq 8-Hour Instead or 18-Hour Periods MATERIAL TEMP. AT.OCPOAWIBCBINtfTBIUO'rXtON TOTAL BXPOBORX EAJVSL.FDGSAOILRY.* *c. m. Pent and hexaehloroaphthalenes..,... 149-193 1.44 90% pent* and hexachlornaphthalenes plus 10% chlorinated diphenyl.......... 150-197 1.66 Chlorinated diphenyl............................. 153-174 0.93 ranf* High 2.58 Low 0,42 High 3.30 Low 0.56 High 3.23 Low 0.03 kmtr# 920 912 920 g 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 work 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- I TOXSTUDIESOOI8 ml 18, no. 7) EFFECTS OF CHLORINATED HYDROCARBONS 297 carbons may often be made by simple feeding and do not require the elabo rate apparatus and the expense neces sary for inhalation experiments. The essential reason for this opinion resides in the identity of the lesions produced by both methods, and the fact that the different compounds so far studied seem to arrange themselves identically so far as toxicity is concerned which ever way they arc administered. Trichlarnaphthoiene plus traces of tetmchlornapklhalem.--Feeding began on May 4, 1936 and continued until November 2,1936. In the begin ning 3 gm. of this mixture were added to the food for 10 rats each day, and this concentration was maintained throughout the experiment. All the animals were killed except the last which died on Nov. 2. There was no loss of weight and no appearance of wasting illness of any sort. The single death was due to some variety of re spiratory infection which had no rela tion to the material inhaled. Histological examination showed slight changes in tiie liver but nothing of great significance. Tetra and pentachlomaphlhalenes.-- Feeding began on June 29, 1936. A dosage of 0.5 gm. daily was employed. Alt the animals sickened gradually and were either killed or died by August 29,1036. ' At autopsy both grossly and histo logically the liver was the single organ affected. The liver cells showed swell ing, hypergranulation, hyaline inclu sions and vacuoiation. Here and there necrotic cells were found. There was a tremendous accumulation of fat. Penta and hexachlomaphthalenes.-- Feeding began May 4, 1936, a 3 gm. dosage being used. By June 6, nine rats had died. The last one was obvi ously ill and was killed for autopsy examination. All animals lost weight from the beginning and were ill. At autopsy the liver alone was affected, the lesions observed being similar to those that have been described for tetra and pentachlomaphthalenes but worse. 90 per cent penta and hexachlornaphthaknes and 10 per cent chlorinated diphenyl.--Feeding began May 4, 1936 on a 3 gm. dosage. On May 16th feeding was stopped but all the animals went on to death, the last dying on June 8th. An autopsy the liver lesions were extremely severe and of the usual type. On account of the high toxicity of the 3 gm. dosage, four rats were given a 0.5 gm. dose every other day. Feed ing began June 24, 1936 and the last animal was killed Sept. 11th. There were no deaths but all the animals lost weight. At autopsy the liver as usual was the single organ affected, the lesions being characteristic and ex tensive. Chlorinated diphenyl.--Feeding be gan May 4, 1936 on a 3 gm. dosage and was discontinued on May 10th. Seven of the 10 rats were dead by May 12th. The throe remaining rats gained in weight but were sacrificed for autopsy purposes on July 8th, The liver changes began at once. There were no changes in other organs. A second group of 10 rats was fed a much smaller dose--0.5 gm. every other day. Feeding began May 20, 1936. The first rat died on May 29th and four more before June 24th. The remaining were sacrificed. Those rats that died showed losses in weight, while those sacrificed had recovered 298 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sepl. 1937 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 hexachlornaphthalenes 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 .. Summary of gross feeding experi ments.--Of the various materials fed rats in large doses trichlornaph thalene the liver was the sole organ affected and the lesions were those already described many times. plus traces of tetrachlornaphthalene Discussion was quite innocuous. Tetrn and pentachlornaphthalcnc showed definite liver damage. Penta and hexachlornaphthalcnes caused a similar grade of injury. The addition of chlorinated diphenyl to penta and hcxachlornaphthalenes increased the toxicity. Chlo rinated diphenyl alone produced liver lesions but in the dosage used was less effective than when mixed with highly chlorinated naphthalenes. In no case did the compounds used produce acute yellow atrophy but the lesions ob served indicate this might be possible if one found a dosage which could act for the proper period of time. These experiments leave no doubt as to the possibility of systemic effects from the chlorinated naphthalenes and chlorinated diphenyl. As in the case of the effects upon the skin, the degree of chlorination seems to determine the systemic toxicity, and it is a striking thing that when trichlornaphthalene is reached systemic effects are never marked and are produced with the greatest difficulty. It is most remark able, too, that all the compounds tested'attack the liver and the liver alone. During the past few months we have determined the organically combined chloride in the livers of ani Feeding Precise Doses by Stomach Tube mals very severely poisoned by penta 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 assuming an air concentration of 20 mgm. per cu. m, was first calculated and reduced to milligrams per kilo and hexachlom&phth&lenes but have found no increase over normal figures, though the livers, .as determined histo logically, were very severely affected. At the present time we arc conducting inhalation experiments on a chlorin ated diphenyl containing 58 per cent gram. The rats and rabbits received of chlorine instead of 64 per cent as this dose each day. The compounds in the case of the experiments reported used were those employed in the gross in this paper and on a compound with ,ii : feeding experiments and the. results a chlorine content between tri and were essentially similar though the tetrachlornaphthalene. We are also lesions were less severe. determining the degree to which the diet may increase or decrease toxicity, Subcutaneous Infections this being suggested by similar work The same gum acacia suspensions upon carbon tetrachloride. were injected subcutaneously into rats In the basis of these experiments TOXSTUDIES0020 vol. 13, no, 7\ EFFECTS OF CHLORINATED HYDROCARBONS 299 and on many field determinations of different compounds in the air of work rooms, it appears safe and it is cer tainly easily attained, to ventilate so that the air breathed does not contain more than 0.5 mgm. per cu. m. of any of these compounds above trichlornaphthalene. In the case of the latter compound concentrations of 10.0 mgm. are permissible. We know from many examinations in many different plants that such concentrations have 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 arc convinced they are safe. Impregnating tanks and other arrangements utilizing the chlorinated hydrocarbons are easy to hood and to safeguard. Compared with benzene, lead tetraethyl and many other com pounds, these substances are very little toxic and operations employing them can easily be safeguarded. It may be argued that where possible trichlornaphthalene should be used, but this compound will cause acne and if employed very carelessly might do more. Furthermore, higher chlorina tion is often essential for highly prac tical reasons. The solution consists in thoroughly adequate ventilation plus good housekeeping around all wax 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 be better to dispense with car bon tetrachloride and depend on other solvents, especially upon those con taining no chlorine. BIBLIOGRAPHY Coubtois-Soffit: Etude sur 1'intoxication professionnclle pat le trichloronaphtalfene. Ann. dc mfcd. Itgale, 14, 422 (1934). Abetr. of paper by Toueaine, A., and Mntrel, B.: Dermatoses profesaionncllcs par la naphtaline et ses derives. Prat. mfcd. Irani;,, 15, 335 (1934). Flinn, F. B,, and Jabvik, N. F.: Action of certain chlorinated naphthalenes on the liver. Proe. Soc, Exper. Biol. & Med., . SS, 118 (1836). Lehmann, K. B.: Kurzea Lehrbuch der Arbeits- und Gevrerbehygiene. S. Hirzel, Leipzig, 1919 (p. 251). Mittelstadt, O.: Gewerbese hiidigungen durch Haftax (Trichlornaphthalin). Inaug. dissert-, Jena, 1935. Tebbens, B. D.: Portable combustion ap paratus for field determinations of chlorinated hydrocarbons. This J,, 19, 204 (1937). Teleky, L.: Die Pernakrankheit (Chloraene). Klin. Wchnschr., 6, 897 (1927). Tooraine, A,, Solente, M#.ntbel, B., and Aubecn : Cinquante-quatre eas de dermatites par trichloronaphtaline. Bull. Soc. dermat. et syph., 41, 265 (1934). r- 300 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY (Sepf. m7 Discussion Db. Cecil. K. Ditmxsit: We have had incline them to. First of all I shall ask quite a long morning, but since Dr. von Qet- Dr. Sayers if he will open the discussion tingen has to leave, I am going to ask him for us. to say a word. Db. R. R. Satbm (Chief, Division of Dk. W. F. you OrrriMMN (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 hie group on the Gentlemen: It gave 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 so that the dangers which apparently the Halowax Corporation, have discussed are connected with the use of this material this matter with us, m well as the manu can be controlled. facturers of the diphenyls. Ijcrfionallv believe that there is no tosic We have been doing some work but not material which cannotbe 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 j iar with the toxicity and especially with the that we can very well keep in mind. I ` mechanism of the action. Since there is no I We are dealing with toxic substances, but J animal which corresponds in all its physio we are dealing with toxic substances each.! logical characteristics to the human being and every. day in industry--harmful sub it is important that such compounds be stances, hazardous substances. "That these studied with different species of animals so can be controlled is well known, no matter that one can get a cross-section of the poten what they are, and that we can use them and tial dangers. 1 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 are 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 does 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 successful. We have got to work together whether we like it or not, I hap Db. Cecil. K. Dhihkeb: In this discus pen to like it. ft]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 notes rials are concerned I think we oughFuTbe TOXSTUDIES0022 Ml- 19, no. 71 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 say approximately 167 because they were never just sure whether it was 167 or 16S. It might have beer, one or two more hut 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 be Bet it on fire with his car bide cap-lamp. The carhon monoxide from the fire killed those men that were in that mine. Many of course escaped. Here we have one h&rard, a fire hazard. Now we have another one, a health haiard due to the toxic materials. We have, to evaluate them. Certain of these materials, I am informed, are also fiammable. I am not just sure how flammable they are but flammability probably decreases as your chlorination increases. But your toxicity also increases as your chlorination in creases, according to Dr. Drinker, and I think that checks with other findings. We 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 I 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. Dm. CecilK. Dsnss: Dr. 'Gray, would you care to say a word? Du, Albert 8. Ghat (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 say 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 elicited 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 be confessed that the amount that he had given the cats and hia 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, we probably wouldn't have liver damage. That is what we did entirely empirically. I think that is about all I have to say. 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. We have been de lighted to listen to the discussion. Dr, Cecil' K. Duxxn: May we now make the discussion general and those who have questions please volunteer. Mr. Manfred Bowditch (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 cose but in the case of other toxic substances with which we 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 will 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 worded warning letter to all plants using these substances and it has all along 302 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY ISept. W$J been my plan to follow that up with a fur ther letter bringing the situation as we now know it, aa a result of Dr, Drinker's work, to the attention of user* in this state. In that letter we shall unquestionably advo cate the concentrations that Dr. Drinker has suggested this morning. 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 Haiowax Corporation is a progressive con cern and it is going to be putting out bigger and better halowaxes ail the time. The company's cooperation in this present Inves tigation has been such that I fee! 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 care to say anything about that. Mr. Sandforo Brown (President, Halowax Corporation, New York, X. Y.): There are some aspects of this situation on which I think 1 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 spend $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 it? 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. That 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 trichlomsphthaienes. 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 to a cable manufacturer. It is composed of certain constituent*. There may be some tetrachlornaphthalene, trichlornaphthaiene, 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 1 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, 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 W TOXSTUDIES0024 vol. 18, no, TJ EFFECTS OF CHLORINATED HYDROCARBONS 303 J with which ail manufacturers of chemicals are confronted today, particularly in the ( synthetic organic field where the develop ment is .so rapid that our sales departments can't even keep up with the research depart ments sometimes, in knowing what they are doing. Mb, F. R, Kaimer (Assistant to Man ager, York Wireworks, Genera! Electric Co,, York, Pa.): I am certainly pleased to have this opportunity to say 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 If 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 may have attrib uted 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 examina tion 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. How ever, it was only for a 0 months' period from the time of his employment that he com plained of this constipated condition and we advised that be 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 condi tion 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. We 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 of all the efforts we have made through our own research laboratories to find one. But we did develop--and I was moat 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. O. 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, we have in this year and a half brought each and every man back to a normal skin condition. Those who were very seriously afflicted do show gears, 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 em 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, either from solution, from solid compounds or handling the wire insulated and treated with it, is examined twice yearly with a com plete 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 r 304 JOURNAL OP INDUSTRIAL HYGIENE AND TOXICOLOGY (Sepf. mi to u* all in industry if some very funds- Springfield, Mass.): Do I understand you mental work was done on humane, as Dr. to say that those men who were afflicted Jones mentioned before we came into this are hack on the same job? meeting, some control in fundamental work to determine some method whereby we may Mb. F. R. Kaimeb: They all returned to determine the inception of any liver dis normal skin health, as I say, and are work order. ing on the same job. We have had our men examined in groups three times since the trouble developed and Dr. Cecil K. Drinker : Dr. Schwarts, nothing hae 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 Da. Louis Schwarts (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 Dr. Cecil K. Drinker: Can you recol it was only because of roy researches in that lect the air concentration that you are main field that I happened to eome 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. P. R, Kaimer: 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 all get 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, dones won't have any scars. reduced with solvent to a paste form, and it As far as prevention goes, I felt even be was not known that it contained a chlorin fore this investigation was undertaken that ated solven t in certain percentage. We dis this substance, like any other poisonous covered it only recently through the analy substance, can be handled and used in in sis of a sample and we found that that was dustry provided proper safety precautions the cause of throwing the results off to a high are taken, and I so advocated at the meeting value. It was then about 3 mgm. per eu. m., in Pennsylvania when this was discussed. I believe. That is going to be eliminated About ventilation and safety precau now. That is a combination of toluene and tions, I think that while we cannot, with our carbon tetrachloride solvent. When that present knowledge, detect by any chemical compound is exposed to the air the chlorin tests the early symptoms of intoxication ated solvent odor is completely masked by from this substance, the skin offers an easy the toluene. It is lost. I waa able to detect way of proving whether your method of it only by removing the head of the drum ventilation is efficient or not. If there are and immediately smelling the odor of carbon any cases of acne or of this dermatitis occur tetrachloride. As soon as that head was ring in a plant where halowax or the chlorin removed for a period of 10 seconds the tolu ated naphthalene or chlorinated diphenyls ene predominated and we had no knowledge are used, then that shows that there is suf- of the other being in there. . ficient concentration of these substances in the air to cause plugging of the follicles and Mr. Arthur G. Beyer (Research Engi to cause a skin condition. If there is suffi neer, United American Bosch Corporation, cient concentration to do that there may he TOXSTUDIES0026 ml. 18, no. 7J EFFECTS OF CHLORINATED HYDROCARBONS 305 sufficient concentration to cause systemic poisoning in the few people who are hyper sensitive to the action of these hydrocar bons. Everybody is not hypersensitive to them. If they were, of the thousands of people who have been handling these sub stances, mors would have contracted this disease and it would have been reported very much earlier. This material was used in Germany as early as 1914 or 1915. While I cannot add anything to the methods outlined here for safety in the way of ventilation and so forth, I can say that if you go into a plant and find that there i# any acne present among the workers with this material you will know that there is sufficient of the substance in the air to cause acne and consequently sufficient perhaps to be dangerous to the few people who are hypersensitive to its action. Dr. Cecil K. Drinker: There is a prac tical pointin regard to the question of deter mining these substances in air. My brother pointed out this morning that there are several pieces of apparatus for doing this. It has seemed desirable to a number of the men who are here that during the next cou ple of years, while we are in a position of learning, that we endeavor, if we can, to confine our analyses to one piece of appa ratus, so that at least our results will be as comparable as we can make them from place to place. 1 don't know much about this phase of the subject: perhaps, Mr. Cook, you have an idea or two about that. M*. Warren A. Cook (Chief Industrial Hygienist, Bureau of Occupational Dis eases, State of Connecticut Department of Health, Hartford, Conn.). On the deter mination of the halowax I wonder if it wouldn't be preferable to have Mr- Hemperiy discuss the method he has been using throughout the country for the determina tion of chlorinated naphthalenes. Dr. Cecil K, Drinker: I think so far as that is concerned it is best to leave that to discussions with Mr. Hemperly and Dr. Brandt afterward. But the question of determining some uniformity of technic for a while at least is, 1 think, a matter of gen eral interest to us. Mr. Warren A, Cook: I am not quite sure that I have in mind exactly what you want in that regard, In connection with sampling? Dr. Cecil K. Drinker: Yea, In con nection with the whole technic of determin ing the material in air, length of sampling, type of apparatus, and so forth. It has been suggested that we endeavor to agree upon some uniform procedure for that and as figures begin to come in, as they will in the course of the next couple of years, we will at least have them on a comparable basis. Mr. Warren A. Cook: In that regard there is no question but what the determina tions and results of analyses of the concen tration of injurious materials in air, corre lated with pathological findings or freedom from pathological findings, are real factors in further substantiating toxic limits which are originally given us from animal experi mentation. In order to obtain data which are of value along that line it is desirable to know to what extent, in terms of milligrams per cubic meter, workers are exposed to in breathing any potentially injurious material. It seem* to me that one of the things that should be done, which many of the plants and many of the organizations equipped to make determinations of injurious materials in air should do, is to make an effort to develop one group and series of results which will represent average exposures of workers to chlorinated naphthalenes. In getting that figure I think that it is of great importance that we should consider average daily exposure. There is a tendency very often in taking samples of air to determine maximum exposures, to get the exposure over a 15 or 20 minute period when the worker may be actually tending a pot where the material is being used, whereas during the subsequent half hour he may be 40 or 50 feet away from that particular location. Therefore, for one thing, it seems to me it would be extremely desirable to obtain in formation in as many plants and as many locations as possible of the average expo sure, taking into consideration not only the worker's maximum exposure while actually P! 306 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY (5*pl, 19ST 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 permits 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 here and one that deserves some study. Dr. Cecil K. Drinker: Would it be of service to the American Public Health 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 he 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-committee: W, A. Cook, chairman, A. L. Coleman, H. B. El kins, W. B. Fulton, S. W. Gurney, E. R, Hayhurst, W, F. Hemperly, F. W. Sehl, and A. N, Setterlind.] 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, Schwarts 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 TOXSTUDIES0028 ml. 16, no. 7] EFFECTS OF CHLORINATED HYDROCARBONS 307 hand, from Dr. Drinker's work one would judge that the straight chlorinated naph thalene waa nearly aa toxic at least as the mixture of it with a smalt amount of chlo rinated diphenyl. In the condenser factory where we had our cases there is no chlorinated diphenyl used and no acne of the type described in the reports on the insulated wire factories. Dr. R. Emmett Kelly (Monsanto Chem ical Co., St. Louis, Mo.): I can't contribute anything to the laboratory studies but there has been quite a little human experimenta tion in the last several years, especially at our plants where we have been manufactur ing this chlorinated diphenyl. It has been our observation that although on one occa sion we did have a more or less extensive series of skin eruptions which we were never able to attribute as to cause, whether it was impurity in the benzene we were using or to the chlorinated diphenyl, we have never bad any systemic reactions at all in our men. We have examined them very closely both from what laboratory tests we thought might help us and from the clinical view point. Also from chlorinated diphenyl alone there have been no cases of systemic poisoning reported. I don't believe that we can transpose the laboratory results into the actual humans without paying considerable attention to the volatility of different substances and the way they are being used. Dr. John A. Hookey (Consulting Der matologist, Halowax Corporation, Detroit, Mich.): I have had considerable experience with the dermatological angle of this prob lem. The experience at the Halowax plant at Wyandotte definitely was that the derma tosis did increase when compounds were used rather than the straight, chlorinated naphthalenes. From the discussion we have heard today I think the observation Dr. Drinker made that the chances are that dermatological problems will disappear along with the other is probably true. However, I think that certain precautions, certain insurance meas ures, you might say, should be taken in hiring men who are going to work with these products, even though we are going to attempt to get the concentrations low. We saw this morning that the effect of these products was on the liver and that if some one working in these products developed liver damage from some other source the chances of his having serious trouble was increased. Therefore, inasmuch as there is no test to tell whether a person has had liver disease, certainly in the preliminary medical examination of applicants for work the his tory at least should be gone into very care fully for a history of previous liver diseases. There are other things that should be taken into consideration also. One is the history of syphilis, because syphilis does have an effect on the liver. If there is any history of syphilis I don't think that that man should be hired. A Kahn test should be taken and I think that it would be a good plan to take Kahn tests on men at stated intervals, because they might develop syphilis alter they are hired. I think those things should be done even though we feel that if the concentration of these vapors in the air is kept as low as was recommended this morning, the chances of having toxic effects are very small. Me. F. R, Kaimer: 1 would like to clarify a point of Dr. Hookey's. You mentioned at the beginning of your talk that your experience in acne condition was more pronounced from the compounds of various materials with chloronaphthalcne than with the straight ciiloronaphthalcnes. Did you mean by that, that the acne condi tion actually was more pronounced with the compounds than with the straight chloronaplitholcnc or was thntductn the fact that you were in a plant operated in a different fashion? In other words, you handled your numerous wire compounds i:: more of a batch operation. That is my understand ing from Mr. Brown. 1b it a fact that the straight chloronaphthalenes are less harmful in so far as acne is concerned or is it because of the handling of batch compounds? Dr. John A. Hookey: That is a question that would be difficult to answer. I based my statement on the fact that in taking a general survey of these cases after 1 started working with them the men in the plant said 308 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY (&pl, 19S7 that they developed acne more often and more eeverely after they etarted making compounds. It may be that it wae in the method of the handling. Mk. F. R, Kaimir; You say that the con dition increase* 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 plasticising agents? How much do we know about those insofar as development of acne is concerned? Some of these compounds have a half dozen con stituents in them other than chlorodiphenyl and chloronaphthalene. We are at the present time considering the chloronaph thalene as the basic element responsible for the acne condition which we have. We know very little about what the other mate rials may or may not do, Dr. John A. Hooket: I don't know about theae other materials. Perhaps Dr. Schwartz would know something more about them. Dr. Lotus Schwartz : It is well known in industry that there are many compounds that cause acne. For instance, paraffin acnea and oil acnes have been known for a long time. Paraffin acnea, wax acnes, are simply a mechanical plugging of the fol 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 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 comedone and then the comedone becomes infected and forms a pustule. They don't all pustulate because they don't all become infected. Many of these men never have any pustules. They 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, acne vulgaris is most apt to occur. The sebace ous gland* are most active and they seem to have it much more than the older people in whom the sebaceous glands are not so 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 ated naphthalenes or diphenyls but can occur with any condition that blocks up the sebaceous follicles of the skin. Dr. Rotal Meeker (Special Agent, State of Connecticut Department of Labor, Hartford, Conn.); I am full of questions. As a statistician I am a little bit suspicious of averages, so I should think that we should take maxima as well as averages in getting at the threshold dose or the dangerous im pregnation of the atmosphere with these poisonous compounds. I just wanted to drop that as a hint for this committee to consider in its work. In spite of what you said at luncheon, Dr. Drinker, I still think it is rather impor tant to determine how the plugging of the pores actually does occur, whether they are plugged as Dr. Schwartz has suggested, from the particle* falling on the outside of the skin or whether they are 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 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. I haven't heard anybody say anything about those Massachusetts cases of very severe dermatitis and I am not so sure but what there was some question of liver dam age there. Nobody has said anything about them at all. There is no question there TOXSTUDIES0030 pel, IS, no. 71 EFFECTS OF CHLORINATED HYDROCARBONS 309 that the condition, whatever the complica tion* might have been, came from handling cold wire, in a confined area of course, I think this need* a great deal more study, Dr, Drinker, than you and your associate* have been able to give it a* yet. All I am curious about it 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 hatowax, chlorinated naphthalene and diphenyl. It seemed to me that they left very much to be desired. I don't gee 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 Rockbesto* Products Corporation to tell how they have handled it. If 1 am any judge of equipment and safety devices they have come as near to eliminating entirely from the atmosphere all contamination from fumigated or evapo rated halowax at anyone. All of the appli cation of halowax, either in the melting pots or where it is applied to the wire, is done under hooding and with ventilating appa ratus, and it teems to be entirely adequate. wax we had a head start as far at the ventilating system was concerned, since ours was already installed and adaptable to a compound with a benzene solvent rather than a melted 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 tame 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 be opens it he increases the amount of air travel about ten-fold. Dr. Royal Meeker: What is the veloc ity when the door is open? Mr. B. H. Reeves (Vice-president and General Manager, Rockbestos Products Corporation, New 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's 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 1023 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 tame fix as every one else is as far as finding a substitute for halowax. There is none that we know of. Con sequently when we went to the use of halo- Mr, B. H. Reeves: With the door wide open, at breathing level the velocity is 200 feet. That ia the linear velocity. We check that every week on every opening at every machine with a veiometer, 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. Rotal Meeker: What do you think of that trap device shown? Mr. B. H. Reeves: 1 don't know what to think of that. I don't know whether it would be practical or not. I was going to aek Dr. Drinker whether in passing the air laden with halowax fumes through the boxes of rats there was any deposit of halowax in the enclosure. 310 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY (Sept. 1837 Dm. Cecil K. Drinker: Ye*. It is detectable readily through the outflow pipe. Mr. B, H. Reeves: Those in the for end probably didn't get the concentration. Da. Cecil K. Drinker: We change the poaition of the boxea each day. The ones furthest away move Into the nearest poai tion, so that over a period of weeks all are exposed equally. complaints were bona fide. We had no dif ficulty in handling cold wire and the men had no skin trouble. Yet when they did the same thing with possibly the application of heat in tunnels, ships and so forth, they actually did develop trouble. " We have used, of course, the Icterus index in following some carbon tetrachloride cases and I wondered what you have to say about that. Is that of no value at all in the case of liver damage in this material? Dr. Euert R. Haykurst (Consultant In Industrial Hygiene, State Department of Health, Columbus, Ohio): I would like to ask if it wouldn't be possible to put a cold water line around that trap and deposit it all before the air escapes from the trap. Mr. B. H, Reeves: We have tried cool ing the surface of the exhaust pipes in order to concentrate the deposit in one place and make it unnecessary to remove long lengths of the ventilating system. While we have found a slight advantage in doing so it hasn't at all paid for the expense. It is much easier to take the piping down. Con sequently I doubt the possibility of remov ing it all by cooling the surfaces of the trap. It might be possible, by building a labyrinth of refrigerating coils, to collect it. But then you would have the problem of remov ing it from the coils after you had collected it and it would involve rather complicated procedure. Dr. B. L. VosBtmcH (Medical Director, General Electric Company, Schenectady, New York): We have heard about the pos sibility of preventing liver damage and akin trouble among manufacturers of wires and cables and so forth, but like the old rhyme, every dog has fleas and the fleas have fleas, we also have customers who use wires and cables in tunnels, in enclosed spaces, splic ing them together and doing all sorts of things. I am not at all certain that we know what the concentration of these chlorinated hydrocarbons is under those conditions. About the time we were having bo much trouble at our York factory some of our customers began complaining. We thought we were having a hysteria of halowax mania throughout the country. Some of their Dr. Cecil K. Drinker: I don't think so until it gets so extreme that we know it any way. Dr. B. L. Vosbdrcih: I did write down a few questions that came to mind. Some of them have been answered and some are foolish but 1 shall ask them anyhow. It occurred to me that if trichlomaphthalene has been proved to be practically innocuous, isn't it a problem of research largely for the Halowax Corporation to use only that one material adopted with other known chlorinated compounds to meet the requirements of customers? That is one of the foolish ones probably, but I shall just ask it. Furthermore, how long is it reasonable to expect the liver to recover after it has been pretty well damaged. I talked to you and you said you hadn't worked that out with the animals ae yet. Dm. Cecil K. Drinker: In that case we set aside a certain number of animals to recover, after knowing that a certain amount of damage had been done. Then we started to kill them but we invariably ran out of rate before they ran out of lesions. We don't know how long it lasts. Dr. B. L. Vosboroh: Have you given them calcium and glucose as you would with carbon tetrachloride? Dr, Cecil K. Drinker: Not yet, but we are doing an experiment now with one group on a very high calcium diet and another group on a calcium free diet. The whole question of calcium in the diet, of giving milk daily to these people may be worth while. TOXSTUDIES0032 Ill>1. IS, no. ?] EFFECTS OF CHLORINATED HYDROCARBONS 311 Dr, B. L, Vosburqii: 1 just had those question* in mind. 1 would like to hear what Mr. Brown would say as to the possi bility ot using only -this one innocuous chlorinated naphthalene. Mr, Sandforo Brown: That would simplify our problem exceedingly, not only from the commercial standpoint but from the toxicity standpoint. But if we did so I think that Mr. Kaimer would be the first to object because he wouldn't be able to get the technical effects he desires in the cable. The same thing applies throughout all the industry where we are using these higher chlorinated products. The problem as we see it, and it is one which we intend to study further (we have our program for this continuous work that will be done under the direction of the Drinker brothers), is to try to find a line of demarcation and whether or not within this complicated chemical structure there is some one thing that causes the trouble. If we could take hexachlorn&phtbalene and remove 1 per cent of some unknown constit uent with which we arc not now familiar and eliminate the toxicity, that would be a lovely solution. Whether we will ever be able to attain that I don't know. That is one of the things we have in mind. As I said before, that is one of the things with which all manufacturers of these syn thetic organic products are confronted at some stage, either in their laboratories or in commercial developments. It is largely a question of timing as to when you should do the work, how much you should do, and whether you know how to do it. You have to learn that first. Dm, Cecil K. Drinker: Unless there is some other important matter I will declare the meeting adjourned. De, R. R. Saters; May I say a word more with regard to what Dr. Hookey stated on syphilis? If you are going to eliminate all your workers who happen to develop syphilis during the time they are working for you, you are probably going to lose some very important employees. It would seem that it would be worth while to give serious consideration to seeing that conditions are proper and suitable for them to continue working for you and that they have proper treatment. In other words, I don't believe that is a good or sufficient reason for dis charging those employees who do develop syphilis. We have not found that to be true in other places and I question whether this is one of the places. I may be in error. Mr. Sandford Brown: I want to take this occasion to express on behalf of the Halowax Corporation my thanks for the excellent cooperation we have received from various state authorities and our customers as well in this investigation. I believe you have all formed the opinion, based on what you have heard this morning, that our whole motive here is to conduct this on an ethical, scientific and constructive basis. In collaboration with the Monsanto Chemical Company we have a much more comprehensive program in view to carry on. Therefore we want to continue that same type of cooperation. There is one thing that I want to bring up in that connection, which will have to be observed by the state authorities, when they go out to make these inspections. That is the necessity of not creating mob hysteria on the part of the workmen in the plants where these inspections are made. Mr. Hemperly has run into some very interest ing situations in the various examinations he has made. I know that he would be glad to relate them and give the benefit of his experience to the heads of any of these state departments who will have the direction of this work. Otherwise I can see where we will be unable to get the full cooperation of not only the individual workmen but the plant foremen and the management, and we must have that if we are to get the results that we are shooting for over the next sev eral months or years. This thing may con tinue, probably will continue for years.