Document NEz0VOQKvwBR3QgDzjE1O9aQg

PLAINTIFF'S E EXHIBIT P - 11a 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. mHE use of chlorinated naphtha rapidly and thoroughly as possible.! . I lenes and compounds of allied In brief these cases were as follows: -**" pharmacological possibilities is extremely wide, and with the steady growth of the use of electricity is cer tain to expand much farther. For years it has been known that many of these compounds cause a troublesome acne, and there is a large literature upon this phase of the subject. Our investigations have not been concerned with chloracne but with the possibility of systemic effects following ingestion Or inhalation of such products. In the Patient 1. Male, age 21. The previous medical history of this man was in no way significant except for the fact that he had an attack of jaundice about 6 weeks prior to his fatal illness. Late in December, 1936, he became badly constipated and had much abdominal pain and distention. When ad mitted to the hospital he was slightly jaun diced and was evidently very ill. He was somewhat anemic and his skin, particularly upon the arms, face, chest and back, showed many pustules. He died after a brief period in the hospital, and at autopsy was found to spring of 1936, the Halowax Corpora tion, a division of the Bakelite Cor poration, called our attention to three fatal cases of jaundice in workmen using chlorinated naphthalenes and chlorinated diphenyl, and requested that the subject be investigated as * Received for publication June 30, 1937. f The Halowax Company makes many products besides chlorinated naphthalenes, and it has come to our knowledge that all of these products are indiscriminately called "halowaxes" by purchasers and users, and are 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. 283 P 11 PLTEXP010340 284 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. 18J7 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 who had been exposed to trichlornaphthalene. Of these 13 were found to have mild digestive complaints, anorexia, nausea and vertigo, but approximately 10 per cent of a refined chlo rinated diphenyl. While both he and others engaged in the same work had chloracne, there were no other disturbances of health in fellow workmen, nor was there any pre cipitating cause for the acute yellow atro Courtois-Suffit remarks finally, "Ab 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 a phy such as treatment with arsphenamine or exposure to dangerous concentrations of carbon tetrachloride. Patient 2. This was a young man who died in February, 1936, after an acute illness characterized by jaundice. He had been to be of little consequence considering the mildness of the digestive troubles and the absence of respiratory phe nomena." In Touraine's cases the exposure was 4 exposed to fumes arising from a mixture of penta and hexaehlornaphthalenes. 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. to a trichlornaphthalene, whereas the American cases of acute yellow atrophy were exposed to compounds of higher 1 chlorination. Our own experiments indicate that trichlornaphthalenes 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 beyohd ',' anything encountered in industry, in *; order to produce liver damage. Tel- eky (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 these three very re chlorine content the less the acne. cent fatalities, we have learned of four Mittelstadt (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 but 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: vol. IS, no. 7! EFFECT; 1. A mixture of tri a naphthalene. 2. A mixture of teti chlornaphthalern 3. A mixture of per: chlornaphthalern In addition, sublimate (3) were collected in oi subcutaneously. None of the animals r the sublimate from (2) < after 2 months were quit autopsied. The first de mals receiving (3) occurr day and the last died on Those receiving the subl were even more seve Autopsy in these anil striking changes in the described, entirely chi acute yellow atrophy b suggestive to cause the a dude that "certain chic thalenes or impurities them are capable of prc atrophy of the liver in tl At the beginning of Flinn and Jarvik (1936 fact that there have be of acute yellow atroph in men working with chl< thalenes but give no do to them. These cases ai the same as those dot beginning of this paper. One may summarizi literature upon systemi these substances as foll< 1. With the exceptio tion of acute yellow atr and Jarvik (1936) there or even suggestions of upon human beings. 2. There is evidence that the degree of chlo PLTEXP010341 1 D TOXICOLOGY [Sept. l9S7 been exposed to trichlorne. Of these 13 were found mild digestive complaints, nausea and vertigo, but iuffit remarks finally, "Ab s certainly possible and we iroof of it some of the digesgeneral complaints which due to it. But they appear ttle consequence considering ess of the digestive troubles ibsence of respiratory phe nine's cases the exposure was lornaphthalene, whereas the cases of acute yellow atrophy sed to compounds of higher nil. Our own experiments , hat trichlornaphthalenes rermous dosage, far beyond encountered in industry, in Droduce liver damage. Tel ) reported a number of cases me in persons exposed to d naphthalenes with a chlo-r nt ranging from 14 to 53 per* found that the lower the:ontent the less the acne. It (1935) examined a number f chloracne due to trichlor-, ne and reported a number of eral complaints but nothing ure of serious disease. Re is animal experimentation, (1919) reported that aniLlorinated naphthalenes reiat after a time and that, oisoned by inhalation or by t death showed "peculiar" ;he liver. Flinn and Jarvik e subcutaneous injections of doses of chlorinated naphtissolved in paraffin oil to The compounds used were vol. IS, n0 effects of chlorinated hydrocarbons 285 m mft 1. A mixture of tri and tetrachlornaphthalene. 2. A mixture of tetra and pentachlornaphthalene. 3. A mixture of penta and hexachlornaphthalene. In addition, sublimates from (2) and (3) were collected in oil and injected subcutaneously. None of the animals receiving (1) or the sublimate from (2) died, and even after 2 months were quite normal when autopsied. The first death in the ani mals receiving (3) occurred on the 12th - day and the last died on the 26th day. Those receiving the sublimate from (3) were even more severely affected. Autopsy in these animals revealed Striking changes in the liver, not, as described, entirely characteristic of acute yellow atrophy but sufficiently suggestive to cause the authors to con clude that "certain chlorinated naph thalenes or impurities contained in them are capable of producing yellow .atrophy of the liver in the rabbit." At the beginning of their paper, Flinn and Jarvik (1936) mention the fact that there have been three cases of acute yellow atrophy of the liver in men working with chlorinated naph thalenes but give no details in regard to them. These cases are undoubtedly the same as those described in the beginning of this paper. One may summarize the meagre literature upon systemic effects from .these substances as follows: 1. With the exception of the men tion of acute yellow atrophy by Flinn and Jarvik (1936) there are no reports or even suggestions of serious effects upon human beings. 2. There is evidence (Teleky, 1927) that the degree of chlorination is sig nificant in relation to the production of acne. In the work of Flinn and Jarvik (1936) the compounds produc ing serious liver injury were the most highly chlorinated of those tested, though the chlorine contents as given by analysis vary surprisingly little. 3. There are no published figures upon the amounts of various chlorin ated naphthalenes in the air which will produce injury of any sort, and while the work of Lehmann (1919) and of Flinn and Jarvik (1936) point to the liver as a possible site of injury this indication rests upon such extreme dosage as to fail to apply directly to human exposure. Experimental Work In appraising the possible toxicity of any substance met in industry it is first necessary to determine the prin cipal route of absorption. In the case of the compounds under consideration there can be no doubt that inhalation is their chief means of entering the body. They are used hot in a great variety of operations and volatilize in varied degree. They are often applied in solution in such volatile solvents as carbon tetrachloride and toluene. The amounts reaching the air under such circumstances are hardly detectable. It will however be shown that carbon tetrachloride adds to the toxicity of the chlorinated naphthalenes and allied compounds, and 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 PLTEXP010342 286 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. 193? workmen may be extremely dirty and careless, comparatively little of these waxes is eaten. They are tenacious substances, insoluble in water, and if they get on the hands they stick there and 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. tion. They thrive upon a diet very similar to man, and in the case of these chlorinated compounds it is possible that diet may be very significant. Finally, their normal characteristics have 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 Fig. 1. Front view and inflow end of two boxes with rat cages in place and doors open. Inhalation experiments are then the most important sources of information, but to them we have added a certain number of observations upon ingestion and subcutaneous injection of various compounds. Inhalation Experiments Animals.--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). Each box was equipped with an individual variable-speed elec tric blower which blew the air through several feet of 7-inch pipe before enter vol. 19, no. 7] EFFECTS ing the end of the bo> meter was placed in the the flow of air in cubic fe could be adjusted and res from a calibration cur deflector placed at the ei pipe into the box was ar sure a uniform distrib stream of air to the two At the opposite end of outflow end--the air fr was exhausted through fitted with a damper anc a large central exhaust 1 About 4 inches from tl the 7-inch pipe into the I of the substances lister duced into the inflowi daily designed pyrex (figure 4), 7f inches Ion diameter of lj inches, hold the heated w^axes. were made with a side ; that extended to the top of the flask was gro this fitted a short tube length. This short tubt into a large rubber stop] tightly into a hole cut ou pipe on the under side (fi flask in turn was placed heater made to cover below the side arm and top. Rubber tubing c side arm with a compre voir and a gentle strean through the melted w; motion and assured uni Into each flask was insert centigrade thermomete kept in place and could 1 time above the 7-inch which it passed (figure 2 . Approximately 30 gm chlorinated naphthalene PLTEXP010343 TOXICOLOGY [Sepl. 19S7 y thrive upon a diet very nan, and in the case of these l compounds it is possible may be very significant, leir normal characteristics described so well as to make ion of abnormalities both jrtain. f exposure.--The inhalation s were carried out in four ight wooden boxes, each holding ten rat cages, size xges in place and doors open. < 14", in two tiers of five When the experiment was ;ress the doors were opened the cages kept in place mter of one end of each box w end--air was introduced pipe 7 inches in diameter Each box was equipped .ividual variable-speed elecwhich blew the air through of 7-inch pipe before enter ed. 19, no. 7] EFFECTS OF CHLORINATED HYDROCARBONS 287 ing the end of the box. An orifice meter was placed in the pipe line, and the flow of air in cubic feet per minute could be adjusted and read off directly from a calibration curve. A vane deflector placed at the entrance of the pipe into the box was adjusted to as sure a uniform distribution of the stream of air to the two tiers of cages. At the opposite end of the box --the outflow end--the air from each box was exhausted through a 7-inch pipe fitted with a damper and connected to a large central exhaust fan (figure 3). About 4 inches from the entrance of the 7-inch pipe into the box, the fumes of the substances listed were intro duced into the inflowing air. Spe cially designed pyrex glass flasks (figure 4), 7f inches long and with a diameter of 1\ inches, were used to hold the heated waxes. These flasks were made with a side arm and tube that extended to the bottom. The top of the flask was ground, and into this fitted a short tube If inches in length. This short tube was inserted into a large rubber stopper that fitted tightly into a hole cut out of the 7-inch pipe on the under side (figure 2). The flask in turn was placed in an electric heater made to cover it completely below the side arm and ground glass top. Rubber tubing connected the side arm with a compressed air reser voir and a gentle stream of air blown through the melted wax kept it in motion and assured uniform heating. Into each flask was inserted a long stem centigrade thermometer which was kept in place and could be read at any time above the 7-inch pipe through which it passed (figure 2). Approximately 30 gm. of pulverized chlorinated naphthalenes or 20 gm. of chlorinated diphenyl were placed in the bottom of each flask and melted in the electric heater. Fresh samples were used every other day, but it was often found necessary to add 20 gm. of new material even after one run since so much had sublimed. Whatever the case, the collected sublimate was Fig. 2. Electric heater for maintaining chlorinated compounds at a constant tem perature in place at inflow end of box. always removed from the upper part of the flask and a clean top used each day. No sample was ever used for more than two runs. The flask plus the contents was care fully weighed at the beginning of the run and at the end, and the loss in weight used to calculate the average 288 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. 19S7 amount in a cubic meter of air per flowmeter readings. The figures ob minute as determined by a series of tained were not absolute because of slight variations in the air flowing through the boxes and because of deposition of material on the ther mometers and on the inside surfaces of the box, but they cheeked well with direct determinations through air samples. Approximately 1 hour was allowed for the wax in the flasks to melt and come to a constant temperature. At that time the box doors were tightly closed, air bubbled through 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, the amount of air flowing through the boxes was adjusted and an attempt Fig. 3. Outflow end of two boxes showing was made to keep the four boxes as connections to exhaust system. uniform as possible--usually between 165 and 175 c.f.m. In the first group of experiments the following substances were tested: 1. A mixture of trichlornaphtha- lenes plus a trace of tetrachlor- napthalene. Chlorine content 49.9 per cent. 2. A mixture of penta and hexa- chlornaphthalenes. Chlorine content 62.6 per cent. 3. A mixture of 90 per cent penta and hexachlornaphthalenes plus 10 per cent refined chlorin ated diphenyl. Chlorine con tent 63.0 per cent. 4. 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 Fig. 4. Pyrex glass flask in each cage. They were fed Purina vol 19, no. 7] EFFECTS C Dog Chow supplemented eggs, milk and cod liver oi This first group of expel begun on July 1, 1936 ai exposure to number 2 (pent chlornaphthalenes) was on 16th. The exposure to the compounds ceased upon 18th. On October 15th tive animals were taken o sure from groups 1, 2, and killed after 2 months on 15th, in order to see wheth Conditions Maintained in In ?'v. Trlchlornaphthalenes plus tra tetrachlornaphthalene....... Penta and hexachlornaphthal 90% penta and hexachlorna lenes plus 10% chlorinated di m Chlorinated diphenyl. period would bring about the affected livers. An group 3 were similarly re exposure on October 4tl for examination on Decern The average length of c 16 hours daily for 6 di Each morning at about 9 ceased, and between th 4:00 p.m. the rats were weighed, etc. In order t formity of exposure the shifted on a regular scl PLTEXP010345 TOXICOLOGY [Sept. 19S7 ladings. The figures obnot absolute because of tions in' the air flowing e boxes and because of if material on the therd on the inside surfaces of t they checked well with rminations through air itely 1 hour was allowed in the flasks to melt and oust ant temperature. At ic box doors were tightly jbbled through the flasks, /ers turned on. This was g of the exposure period, rheostats on the fans and the outflow pipes, the air flowing through the djusted and an attempt > keep the four boxes as 1 lossiblc--usually between e.f.m. ; group of experiments the istances were tested: lire of trichlornaphtha- plus a trace of tetrachlor- lalene. Chlorine content ier cent. lire of penta and hexa- laphthalenes. Chlorine lit 62.6 per cent, ire of 90 per cent penta hexachlornaphthalenes 0 per cent refined chlorin- diphenyl. Chlorine con- 13.0 per cent, ited diphenyl. Chlorine v it 65.0 per cent, unds were selected as rep ertain range in chlorina- lecause of their industrial In each instance 80 ani- osed, 10 rats being placed They were fed Purina tol. 19, 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 hexa chlornaphthalenes) 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 RINE CONTENT TEMP. AV. CONCENTRATION OF AIR IN BOX Trioblornaphthalenes plus traces of tetrachlornaphthalene................... % 49.9 "C. mjr./cu. m. range 150-160 1.31 High 2 .60 Low 0 10 TOTAL EX POSURE AV. DAILY EX POSURE h0UT8 houn 1896 16 penta and hexachlornaphthalenes.... 62.6 P00% penta and hexachlornaphtha- lenes plus 10% chlorinated diphenyl. k' 63.0 Chlorinated diphenyl......................... 65.0 160-170 1.16 165-175 1.37 165-175 0.57 High 2.19 Low 0.51 High 3.17 Low 0.64 High 1.19 Low 0.23 1864 1896 1896 16 16 16 period would bring about recovery in the affected livers. Animals from lit- 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 16 and 18. The concentration of chlorinated naph thalenes and chlorinated diphenyl in the air of workrooms.--Table 1 shows that animals have been exposed to varied concentrations of the substances under PLTEXP010346 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. 1987 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 and the 30CTI0N 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- PTRFX 7WIN31DE 01Atl. SOLID GLASS B&SPS Ifin DlAM. NOT DRAWN TO 5CALE ^resistance furnace a>Fr NicHBOMewiee (i ohm/ft) quartz: 7MM INSIDE OlAli. platinum foil racking 6" X 15"* 000/" I5.Z.4 *3.81 * 0.00254 CM. Fig. 5. Dimensioned sketch of combustion tube and absorption apparatus. concentrations chosen for inhalation experiments depended on these exami nations. The technic of analysis and the apparatus employed were the work of Frederick R. Millhiser and William F. Hemperly. The method and apparatus used for determining concentrations of chlorin ated hydrocarbons in air were adapted from well-known procedures. The air mined nephelometrically as silver chloride. Tebbens (1937) has recently de scribed a method and apparatus which should be equally satisfactory for this work. In figure 5 we show a dimen sioned sketch of the combustion tube and absorption apparatus as used by us in both our laboratory and field problems. The absorption tube is vol. 19, no. 7] EFFECTS somewhat easier to wash c Tebbens's but the essentia devices are the same.* In both cases conversion rinated hydrocarbons to 1 acid and subsequent ab sodium carbonate should l In our case concentration apt to be very low--the less than 1 mgm. per cu. quently the amount of sil actually formed in the fina so small that it can not be either gravimetrically or 1 For this reason we have be use the nephelometric proc is sensitive to concentrat as 0.1 mgm. per cu. m. of a It is doubtful if the sa should exceed 1 liter per conversion of the chlori pound to hydrochloric a subsequent absorption are unless the velocity of the g low. Another precaution is that the method is nol any chlorinated substan determined. Furthermori distinguish between solid j gases but determines them the results must, of coui puted in terms of total cl At the present time wi formation as to the amoi rinated naphthalenes in t different plants, and in i instances the measuremen repeated several times, the amounts have been ; those used in our experin must be remembered th * The combustion and abs ratus suited to field samplinj by Willson Products, Inc., The equipment includes fl suction pump with a carrying PLTEXP010347 TOXICOLOGY [Sept, iggj s passed over heated platielectrically heated quartz e effluent gas scrubbed in glass beads moistened with onate containing a trace of ite. The beads are then n and the chloride deter- )T DRAWN TO SCALE IM/rr) INS 01" 3.002 54 cm. nd absorption apparatus. dielometrieally as silver (1937) has recently deithod and apparatus which qually satisfactory for this igure 5 we show a dimenh of the combustion tube don apparatus as used by our laboratory and field The absorption tube is vol. IS, no. 7J 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 as conversion of the chlorinated com . pound to hydrochloric acid and its subsequent absorption are not efficient unless the velocity of the gas stream is , low. Another precaution to be noted 1 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 S Willson Products, Inc., Reading, Pa. e_ equipment includes flowmeter and suction pump with a carrying case. have been exposed for 16 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 cases of acne. Results of Inhalation Experiments. 1. Animals exposed to a mixture of trichlornaphthalenes plus small amounts of tetrachlornapthalene. 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 hexachlornaphthalenes. 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 PLTEXP010348 292 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. 19S7 granular cells, hyaline inclusions and mitotic figures, but no more than 2 months previously. 3. Animals exposed to a mixture of 90 per cent penta and hexachlornaphthalenes plus 10 per cent refined chlorinated diphenyl. No abnormali ties were seen in the living animals. After 6 weeks the livers showed changes similar to those in the animals exposed to penta and hexachlornaphthalenes. These advanced in grade during August and September and then became stationary. 4. Animals exposed to chlorinated diphenyl. No abnormalities were seen in the living rats. After 6 weeks' ex posure there was slight liver damage which advanced during the next 2 months. The changes consisted in slight to moderate swelling of the liver cells, an increased granularity and many mitotic figures. Hyalinization was always present as a result of inhalation of chlorinated diphenyl. Summary of the first inhalation ex periment.--In these experiments care ful observation of appearance, body weight, activity, blood, and urine showed no abnormalities of any sort. Yet after 6 weeks' exposure all the compounds with chlorination above trichlornaphthalene caused minor de grees of liver damage, and no changes whatsoever in other organs. There was no acute yellow atrophy or any thing suggesting it except that a slight degree of liver damage was always present and was quite clear in the liver sections examined microscopically. This damage had no detectable effect on the health of the animals. They held their weight, ate and behaved normally, being in every respect similar to the many people who have been exposed to these compounds without illness of any sort. The functional appraisal of the liver damage caused by certain chlorinated naphthalenes and by chlorinated di phenyl.--There are no tests of liver function useful in such minor degrees of liver damage as were produced in these experiments. Indeed the ani mals resisted the injury so perfectly as to display no abnormalities except upon histological examination of the liver. The situation was perhaps similar to that met in industry, where, barring acne, the health of workers in these compounds has been good with the exception of the fact that in iso lated instances jaundice has occurred which upon at least three occasions ` has gone on to acute yellow atrophy. During recent years this disease has " been seen following administration of carbon tetrachloride, arsphenamine and cincophen. In the case of carbon tetrachloride it is known that a low calcium diet and alcohol favor the pro duction of liver damage. For the acute yellow atrophy that occasionally complicates use of the other two drugs no cause can be assigned. One cannot produce acute yellow atrophy with arsphenamine, but somehow or other this now and then does happen to pa tients under antisyphilitic treatment. It occurred to us that something of the same sort might be involved in this problem. The human cases have been scattered and few. They have been isolated instances out of large groups of healthy employees who have had equal degrees of exposure. It was our idea that perhaps many of these people got liver changes such as existed in our rats, changes not recognizable through TOXICOLOGY [Sept. mi these compounds without y sort. ional a-ppraisal of the liver sed by certain chlorinated ; and by chlorinated diere are no tests of liver iful in such minor degrees rage as were produced in iments. Indeed the anid the injury so perfectly y no abnormalities except ogical examination of the situation was perhaps iat met in industry, where, j, the health of workers in lunds has been good with in of the fact that in isoces jaundice has occurred at least three occasions to acute yellow atrophy, cent years this disease has allowing administration of rachloride, arsphenamine en. In the case of carbon e it is known that a low ; and alcohol favor the pro liver damage. For the r atrophy that occasionally use of the other two drugs r be assigned. One cannot ute yellow atrophy with ne, but somehow or other d then does happen to pa r antisyphilitic treatment. ;d to us that something of t might be involved in this The human cases have been id few. They have been .ances out of large groups employees who have had is of exposure. It was our rhaps many of these people ,nges such as existed in our s not recognizable through Jt % pol. 19, no. 71 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 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. 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, 1 died Nov. 13th between 5:00 and 10:00 p.m. 4. Chlorinated diphenyl. Fed at 10:00 a.m., Nov. 10, 1936. 10 rats. 1 killed Nov. 10th at 10:30 p.m. (almost dead). we decided to test their resistance to substances known to cause liver de struction. Carbon tetrachloride and alcohol were selected. Having infor 2 died Nov. 11th between 4:30 and 10:30 p.m. 1 died Nov. 12th before 8:30 a.m. (stiff). 1 died Nov. 13th between 9:30 and 11:00 a.m. mation that 1.0 cc. of carbon tetra 1 died Nov. 16th between 10:15 p.m. 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 Nov. 15th and 9:00 a.m. Nov. 16th (stiff). Controls: Fed at 9:30 a.m., Nov. 12, 1936. 10 rats. 1 killed Nov. 13th for normal liver. 0.75 cc. of ethyl alcohol. This mixture was given by stomach tube to the following groups of ani ' maJs and with the results found in the following tabulation. This tabulation summarizes into the facts that: 1. No normal rats were killed by carbon tetrachloride and ethyl alcohol. 2. No trichlornaphthalene exposed Rati fed 0.75 cc. per kgtti. each of carbon *. tetrachloride and ethyl alcohol by ; stomach tube 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. , 1. Trichlornaphthalene plus trace of tetra- 3. The penta and hexachlorinated ddornaphthalene. Fed at 9:00 a.m., Nov. 10,1936. 10 rats. No deaths. 2. Penta and hexachlornaphthalenes. Fed at 9:30 a.m., Nov. 10, 1936. 10 rats. 3 died Nov. 11th between 4:30 and 10:30 p.m. 1 died Nov. 12th at 3:20 p.m. 1 died Nov. 12th at 4:30 p.m. 1 died Nov. 13th between 9:30 and 11:30 a.m. 1 died Nov. 15th between night of Nov. 14th and 12:30 p.m. Nov. 15th. 2 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. died Nov. 16th between 10:15 p.m. Nov. 15th and 9:00 a.m. Nov. 16th (stiff). 3. 90 per cent penta and hexachlornaphthalenes and 10 per cent chlorinated diphenyl. Fed at 10:00 a.m., Nov. 10, 1936. 10 rats. 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 [NepL 19S7 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 hexacblor- signs of liver injury will be many months in returning to normal. The effect of high concentrations of trichlornaphthalenes with traces of tetra~ chlornaphthalene.--The first group of inhalation experiments showed that this material in concentrations averag ing 1,31 mgm. per eu. 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 ; one of the inhalation boxes was arranged < TABLE 2 Conditions Maintained during Inhalation of High Concentrations of Trichlornaphthalenes plus Tetrachlornaphthalene MATERIAL TEMP. AV. CONCENTRATION OF AIR IN BOX TOTAL AT, J>A1X*T EXPOSURE Expostnui Trichlornaphthalenes plus traces of tetrachlornaphthalene c. mg.jcv.. m. 137-200 10.97 range High 16.49 Low 5.78 hours 1232 hows 16 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 hexachlorinated 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 condition^ 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 pol. 19, no. 7] EFFECTS C in others this did not deve rats were used in this expe one may conclude that wl cblornaphthalenes are in n toxic as those of higher c they are not entirely free f upon the liver if high enou trations are inhaled over lo The effects of high conce. penta and hexachlomap. There can be no doubt as 1 age done the liver by these but in the concentrations ; ported no symptoms were could be recognized clii - nothing approaching ac Conditions Maintained dur Penta and hexachlornaphthat atrophy occurred except Use of the carbon tetrac On December 1, 1936, 8 subjected to the cond marized in table 3. Thi Was terminated on Januar the animals lost weight s and deaths began after 8 c sure. Fifty-five rats dit them heavily jaundiced, i for microscopic examine killed by the carbon tetra and 8 lived through tl exposure. The livers of killed for examination sh< fatty degeneration, cent with necrosis of liver celh animals showed pronounc PLTEXP010351 - TOXICOLOGY [Sept. }gS7 iver injury will be many returning to normal. :t of high concentrations of hthalenes with traces of tetralalene.--The first group of experiments showed that al in concentrations averaggm. per eu. m. of air was innocuous, judged both by :rvat ion and by the carbon de test. This is an in'act since such compounds , though less potently than ; of higher chlorination. ) explore the matter further nhalation boxes was arranged [igh Concentrations op IRNAPHTHALENE WCENTBATION AIB IN BOX TOTAL AV. DAILY EXPOSURE EXPOSURE range High 16.49 Low 5.78 hours 1232 hours 16 nes from four glass containlivered to the air line instead bis resulted in the conditions /able 2. The animals sub:hese conditions showed no ects of any sort. After 1 i liver cells were slightly d over-granular and there onal mitotic figures. These /ere similar to the early more highly chlorinated and progressed only ring the third and fourth ,Vhen rats in this condition carbon tetrachloride and some instances their livers issive central necrosis and vol. 19, no- 7] EFFECTS of chlorinated hydrocarbons 295 jn others this did not develop. Fifty rats were used in this experiment and one may conclude that while the tricblornaphthalenes 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 penla and hexachlornaphthalenes.-- 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 hexachlornaphthalenes are markedly toxic compounds and that recovery from their effects is extremely slow. The effects of penta and hexachlor naphthalenes, the mixture of these with 10 per cent chlorinated diphenyl, and of chlorinated diphenyl alone, when inhaled in low 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 during Inhalation op High Concentrations opTsota and Hexachlornaphthalenes UATERIAL TEMP. AV. CONCENTRATION OF AIR IN BOX TOTAL AV. DAILY EXPOSURE EXPOSURE c. mg./cu. m. Penta and hexachlornaphthalenes........ 137-195 8.88 fc range High 14.0 Low 5.75 hours 608 hours 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. Eighty 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 1. The carbon tetra chloride test was uniformly fatal to them and one must conclude that con- 296 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. 19S7 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 LowConditions Maintained during Inhalation op Concentrations op Three * Compounds during 8-Hour Instead op 16-Hour Periods MATERIAL TEMP. AV. CONCENTRATION OF AIR IN BOX TOTAL AV. DAILY EXPOSURE Expostm* #c. mg.feu. m. Penta and hexachlornaphthalenes......... 149-193 1.44 90% penta and hexachlornaphthalenes plus 10% chlorinated diphenyl.......... 150-197 1.66 Chlorinated diphenyl.............................. 153-174 0.93 range High 2.58 Low 0.42 High 3.30 Low 0.56 High 3.23 Low 0.03 hours 920 lour*. 8 912 8 920 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 m both respects, and indeed one may anticipate that future appraisals of the possible toxicity of chlorinated hydro- vol. IP, no. 7] EFFECTS < carbons may often be mac feeding and do not requir rate apparatus and the ex sary for inhalation experir essential reason for this op in the identity of the lesio by both methods, and the f different compounds so seem to arrange themselve so far as toxicity is concc ever way they are admini Trichlornaphthalene pin tetrachlornaphthalene.--Fcm on May 4, 1936 and until November 2,1936. . ning 3 gm. of this mixture to the food for 10 rah and this concentration wac throughout the experime animals were killed excc which died on Nov. 2. 1 loss of weight and no aj wasting illness of any sort, death was due to some v spiratory infection which tion to the material inhal Histological examinat slight changes in the liver of great significance. Tetra and pentachlorna Feeding began on June ! dosage of 0.5 gm. daily w All the animals sickened p were either killed or die 29, 1936. At autopsy both gross logically the liver was the affected. The liver cells ; ing, hypergranulation, h sions and vacuolation. there necrotic cells were f< was a tremendous aceunt Penta and hexachlorni Feeding began May 4, 1 dosage being used. By PLTEXP010353 TOXICOLOGY [Sepl. WS7 inhale enough of any of inces to get acute yellow 'hey may, however, acquire m of liver damage upon s yellow atrophy may de>erience in a number of shown how easy it is to 3entrations of these com.ctically to the vanishing very effort should be made ch conditions. Feeding Experiments ous compounds used were :nely as possible and mixed idard balanced ration for Concentrations of Thbeb -Hour Periods CENTRATION IR IN BOX TOTAL AV. DAIbT EXPOSURE EXPOSUR1 range High 2 .58 Low 0.42 hours 920 hours . 8 High 3 30 Low 0.56 High 3.23 Low 0.03 912 920 8 8 . >S4 rat. The food was placed container, at which the 10 i cage had an equal chance, t of the compounds added ced as the number of rats uring the feeding period, nents were designed to give to the possible toxicity of inds selected and, if toxicity ed, some idea as to the site iamage. _ "riirients were successful in cts, and indeed one may hat future appraisals of the ricity of chlorinated hydro vol. 19, 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 are administered. Trichlornaphthalene plus traces of tetrachlornaphthalene.--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. |*i'-Histological examination showed ;-Blight changes in the liver but nothing of great significance. Tetra and pentachlornaphthalenes.-- Feeding began on June 29, 1936. A dosage of 0.5 gm. daily was employed. All the animals sickened gradually and were either killed or died by August 29,1936. 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 vacuolation. Here and there necrotic cells were found. There Was a tremendous accumulation of fat. Penta and hexachlornaphthalenes.-- 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 pentachlornaphthalenes but worse. 90 per cent penta and hexachlor naphthalenes 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 Juno 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 three 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 PLTEXP010354 298 JOURNAL OP INDUSTRIAL HYGIENE AND TOXICOLOGY m their initial loss in weight and were gaining. The liver lesions were similar to those found in rats fed penta and hexachlornaphthalenes plus 10 per cent chlorinated diphenyl but not so marked. and rabbits, the dosage being calcu lated on the basis of 4 mgm. per cu. m. of air. Again similar results were obtained. In all such experiments there must of necessity be differences in the degree of effect but invariably Summary of gross feeding experi ments.--Of the various materials fed rats in large doses trichlornaphthalene the liver was the sole organ affected and the lesions were those already described many times. plus traces of tetrachlornaphthalene was quite innocuous. Tetra and Discussion pentachlornaphthalene showed definite These experiments leave no doubt liver damage. Penta and hexachlor as to the possibility of systemic effects naphthalenes caused a similar grade from the chlorinated naphthalenes and of injury. The addition of chlorinated chlorinated diphenyl. As in the case diphenyl to penta and hexachlornaph of the effects upon the skin, the degree thalenes increased the toxicity. Chlo of chlorination seems to determine the rinated diphenyl alone produced liver systemic toxicity, and it is a striking lesions but in the dosage used was less thing that when trichlornaphthalene is effective than when mixed with highly reached systemic effects are never chlorinated naphthalenes. In no case marked and are produced with the did the compounds used produce acute greatest difficulty. It is most remark-' yellow atrophy but the lesions ob able, too, that all the compounds h served indicate this might be possible tested attack the liver and the liver . if one found a dosage which could act alone. During the past few months 1 for the proper period of time. 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 emploj'cd were sus and hexachlornaphthalenes but have > pended in gum acacia. In figuring the found no increase over normal figures, , dosage the total amount a man of 50 though the livers, as determined histo kg. would inhale in an 8-hour day logically, were very severely affected. assuming an air concentration of 20 At the present time we are conducting mgm. per cu. m. was first calculated inhalation experiments on a chlorin and reduced to milligrams per kilo ated diphenyl containing 55 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 : 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 , Subcutaneous Injections The same gum acacia suspensions were injected subcutaneously into rats diet may increase or decrease toxicity, this being suggested by similar work upon carbon tetrachloride. In the basis of these experiments ; tol 19' n0-71 EFFECTS of chlorinated hydrocarbons 299 ftn(j 0n 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 are 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 Courtois-Spffit : Etude sur l'intoxication professionnelle par le trichloronaphtaldne. Ann. de m6d. 16gale, 14, 422 ' (1934). Abstr. of paper by Topraine, A., and M6ntreu, B.: Dermatoses professionnelles par la naphtaline et ses derives. Prat. md. fran$., 15, 335 (1934). Fiinn, F. B., and Jarvik, N. E.: Action of certain chlorinated naphthalenes on the liver. Proc. Soc. Exper. Biol. & Med., $5, 118 (1936). Lehmann, K. B.: Kurzes Lehrbuch der Arbeits- und Gewerbehygiene. S. Hirzel, Leipzig, 1919 (p. 251). Mittelstadt, O.: Gewerbeschadigungen 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 (Chloracne). Klin. Wchnschr., 6, 897 (1927). Topraine, A., Solente, Menetrel, B., and Apbrpn: Cinquante-quatre cas de dermatites par trichloronaphtaline. Bull. Soc. dermat. et syph., 41, 265 (1934). PLTEXP010356 Dr. Cecil K. Drinker: We have had quite a long morning, but since Dr. von Oettingen has to leave, I am going to ask him to say a word. Dr. W. F. von Oettingen (Director, Haskell Laboratory of Industrial Toxicol ogy, Wilmington, Delaware): I wish to con gratulate Dr. Drinker and his group on the very interesting and excellent work on the subject. I also wish to congratulate the Halowax Corporation on the fact that they didn't spare any effort to elucidate the prob lem so that the dangers which apparently are connected with the use of this material can be controlled. I personally believe that there is no toxic material which cannot be used safely if it is handled properly. In order to handle such materials properly during the different oper ations it is absolutely essential to be famil iar with the toxicity and especially with the mechanism of the action. Since there is no animal which corresponds in all its physio logical characteristics to the human being it is important that such compounds be studied with different species of animals so that one can get a cross-section of the poten tial dangers. In addition, this fact illustrates the im portance of the pre-employment and peri odical examination of workers in such work. As was pointed out by Dr. Drinker, there are individuals who are apparently more susceptible to certain toxic agents than others. On the other hand, we have to try to detect the very first signs of incipient poisoning in order to prevent more serious damage. In the present instance it is very difficult to find these very first symptoms because there are no adequate methods, but I trust that in time the scientific profession will supply the medical profession with adequate methods which will allow the physician to determine incipient damage of the organ before serious clinical symptoms become manifest. Thank you. Afternoon Session Dr. Cecil K. Drinker: In this discus sion I will call on one or two individuals and I shall expect others to speak as their notes Dr. R. R. Sayers (Chief, Division of Industrial Hygiene, National Institute of Health, U. S. Public Health Service, Wash ington, D. C.): Dr. Drinker, Ladies and Gentlemen: It gave me a great deal of pleas ure to have the opportunity to listen to the excellent and interesting discussion and presentations made this morning. Dr. Drinker, and I might add, the members of the Halowax Corporation, have discussed this matter with us, as well as the manu facturers of the diphenyls. We have been doing some work but not nearly as extensive as that carried on here. The work that we have been doing seems to confirm the work that Dr. Drinker has car ried on. I think there are certain parts of it that we can very well keep in mind. We are dealing with toxic substances, but we are dealing with toxic substances each and every day in industry--harmful sub stances, hazardous substances. That these can be controlled is well known, no matter what they are, and that we can use them and use them in a safe manner. Dr. Drinker has called your attention to the fact that this apparently has been done and can be done in any of the plants where halowax is used. I have information from one or two of the other men who are in the audience that in plants where damage has been done --skin damage and apparently liver damage to some of the workers--the manufacturers have since corrected the conditions and ap parently have adequate engineering con trol supplemented with adequate medical control. After all, the proof of the pudding is in the eating. If the man does not get the dis ease your engineering control is successful. If he does get the disease, no matter whftt you have done in the way of engineering) you haven't been successful. We must go hand in hand. Neither profession alone can be successful. We have got to work together whether we like it or not. I hap pen to like it. There is one other thing. As far as mate rials are concerned I think we ought to be A\ EFFECTS smart enough to use every on cessfully. If this material i adapted for a certain purpose it. Another material that i vious to this for insulation pi was flammable, caused a disi approximately 167 men lost say approximately 167 beeai never just sure whether it w It might have been one or two were quite sure that 167 lost t happened when they had ins with this material. They ht electric cable. It was cove armor on the outside. It wai and was being lowered into a proximately 3000 feet deep, to a steel rope. It slipped ; bottom of the shaft. When tl inspecting it he set it on fir bide cap-lamp. The carbon the fire killed those men tha mine. Many of course escaj Here we have one hazard Now we have another one, e due to the toxic materials evaluate them. Certain of t I am informed, are also flai not just sure how flammabl flammability probably dee chlorination increases. Bu also increases as your cl creases, according to Dr. ! think that checks with othe have these hazards to balai Control them. I feel quite we can. Perhaps we can find other are better even than this m present time I am advised I better. I am advised that i submarines, it is quite impi non-flammable substance fc of their electrical wire. Dr. CecilK. Drinker: you care to say a word? Dr. Albert S. Gray (L of Occupational Diseases, necticut Department of H Conn.): Dr. Drinker, I dor anything that I can say exc this material in Conneetici PLTEXP010357 vol. 19, no. 7] EFFECTS OF CHLORINATED HYDROCARBONS 301 smart enough to use every one of them suc cessfully- If this material is particularly adapted for a certain purpose we should use it. Another material that was used pre vious to this for insulation purposes, which was flammable, caused a disaster in which approximately 167 men lost their lives. I say approximately 167 because they were never just sure whether it was 167 or 168. It might have been one or two more but they were quite sure that 167 lost their lives. It happened when they had insulated a cable with this material. They had an armored electrio cable. It was covered with lead armor on the outside. It was 1200 feet long and was being lowered into a mine shaft ap proximately 3000 feet deep. It was lashed to a steel rope. It slipped and fell to the bottom of the shaft. When the foreman was inspecting it he set it on fire with his car bide cap-lamp. The carbon monoxide from the fire killed those men that were in that mine. Many of course escaped. Here we have one hazard, a fire hazard. Now we have another one, a health hazard due to the toxic materials. We have to evaluate them. Certain of these materials, I am informed, are also flammable. I am not just sure how flammable they are but 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. Dr. Cecil K. Drinker: Dr. Gray, would you care to say a word? Dr. Albert S. Gray (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 he confessed that the amount that he had given the cats and his method of determin ing it were probably subject to very serious scientific criticism, and we agreed with him on that point. We felt, and I am very glad that it is what you feel as a result of your experiments, that if we put in an efficient ventilation sys tem sufficient to prevent the dermatitis, 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. Drinker: 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 case 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 i 302 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. 19S7 been my plan to follow that up with a fur ther letter bringing the situation as we now know it, as a result of Dr. Drinker's work, to the attention of users in this state. In that letter we shall unquestionably advo cate the concentrations that Dr. Drinker has suggested this morning. One point that I think is worth comment ing on in that connection is the question of identification of the substances. It is ex tremely important from the state adminis trative point of view that employers using these substances should know what they are using. They are identified at present only by numbers. If we list those numbers in a warning letter which we send out there are likely to be changes in those numbers. The Halowax Corporation is a progressive con cern and it is going to be putting out bigger and better halowaxes all the time. The company's cooperation in this present inves tigation has been such that I feel assured that they will take the proper steps to see that we in the state offices and also the users of the products will know what we are using. I wonder whether Mr. Brown would care to say anything about that. Mb. Sandfobd Brown (President, Halowax Corporation, New York, N. Y.): There are some aspects of this situation on which I think I can enlighten the medical and state and civic authorities, with respect to the commercial and practical aspects. If you go into the research laboratories of any large chemical manufacturing company today you will find anything from one to a thousand different new chemical products which have not yet been put on the market. Some of those may or may not be toxic. The problem so far as the chemical manu facturer is concerned is a question of timing. You have heard this excellent presentation given this morning by the Drinker brothers as to the work that they have done here. Should you take a product of which you have developed, say, 5 or 10 gm. and 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 trichlornaphthalenes. 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 constituents. Thera may be some tetrachlornaphthalene, trichlornaphthalene, 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 . vol. IS, no. 7] EFFECTS with which all manufacturei are confronted today, parti synthetic organic field wher ment is so rapid that our sail can't even keep up with the ri ments sometimes, in knowing doing. Mr. F. R. Kaimer (Assi ager, York Wireworks, Gener York, Pa.): I am certainly f this opportunity to say a fi reference to the experience i our York plant. I perhaps s again in this case experience the best teacher. I have : problem at York with the ; through the experience from It is only li years ago tha neighborhood of 50 to 60 me various degrees of this acne a all know. Eight or ten of < severely afflicted--horrible s as their skin condition was ci man died and the diagnosis n uted his death to exposu vapors but we are not sure was an atrophied condition f of the autopsy but we are no that it was or was not con work. Knowing the man a was employed, with the supi tion that he had, he appea thin, pallid in his appearan not say from my poor kn physical make-up of the hi: he presented a healthy app ever, it was only for a 6 mon the time of his employmei plained of this constipated i advised that he see his horn rapidly developed to the po in the hospital and in a ve died. More serious than that pi that we had 50 other men in tion as far as the acne was first reaction that several < had was to throw it out--; plant. They didn't wan that for treating wire. Bu said but not so easily done as well have thrown our bu winds and said, "We'll ch PLTEXP010359 )XICOLOGY [Sept. 1537 :ents before you ever sold >e problem we have had in is been on the market for within the past 4 or 5 years been any intimation that it y systemic effects. Thoumds of workmen have dealt i millions of pounds of certerials, particularly the tri es. Then we come to the ombined with chlorinated ler products, and suddenly resented to us. d various authorities in c health, going back over a 20 years, to investigate it t much enthusiasm for it. iggested that we take it up ;r brothers at this institulid. You know the results is these changes are con s beyond our control to a We will manufacture a all it 1234. It has certain lysical characteristics. It cable manufacturer. It is rtain constituents. There etrachlornaphthalene, tri e, paraffin, a little pitch possibly some chlorinated oes a certain job but he le more plastic or he wants le specific gravity changed, tange in those constituents t we can get that particular an't sell it to him as the we put a new number on it. zer, if the variation in the ithalene or the chlorinated ;uent hasn't changed, the f that will not change. 3 to a question of cooperatte authorities in that con s were some major change ct we would have no hesig them and we would also ners. Virtually every conmaterials at some time or n given their technical or ,tion along with their vari'hether they be physical or e of the practical problems 'J-sj vol. 19, no. 7] EFFECTS OF CHLORINATED HYDROCARBONS 303 with which all 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. Kaimeb (Assistant to Man ager, York Wireworks, General 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 6 months' period from the time of his employment that he com plained of this constipated condition and we advised that he see his home physician. It rapidly developed to the point where he was in the hospital and in a very short time he died. More serious than that perhaps is the fact that we had 50 other men in very bad 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 most closely associated with it--and set up a routine for bringing these men back to nor mal health conditions. A number of them were sent to Dr. John H. Stokes and to Dr. 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 scars, but otherwise their skin is as healthy in appear ance as my own. I tell you we are very proud of the fact that they are still all 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 PLTEXP010360 304 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. 19S7 to us all in industry if some very funda mental work was done on humans, as Dr. Jones mentioned before we came into this meeting, some control in fundamental work to determine some method whereby we may determine the inception of any liver dis order. We have had our men examined in groups three times since the trouble developed and nothing has shown up in any one man. We have learned and appreciate the fact that we must handle hazardous materials, but we have learned how to handle them. It has been a very great experience for us and for myself, and again the best teacher. Dr. Cecil K. Drinker: Can you recol lect the air concentration that you are main taining now with your present ventilating equipment? Mr. F. R. Kaimer: We have had two examinations made of the air by Mr. Wil liam F. Hemperly and they average from 0.2 to 0.6 mgm. per cu. m. We recently dis covered one condition which was found as the cause of a high reading in one of the examinations. The compound is one that is not manufactured by the Halowax Cor poration that is used rather infrequently, perhaps not more than 50 gallons of it in a 6 month period. It is in the form of a paste, reduced with solvent to a paste form, and it was not known that it contained a chlorin ated solvent in certain percentage. We dis covered it only recently through the analy sis of a sample and we found that that was the cause of throwing the results off to a high value. It was then about 8 mgm. per cu.m., I believe. That is going to be eliminated now. That is a combination of toluene and carbon tetrachloride solvent. When that compound is exposed to the air the chlorin ated solvent odor is completely masked by the toluene. It is lost. I was able to detect it only by removing the head of the drum and immediately smelling the odor of carbon tetrachloride. As soon as that head was removed for a period of 10 seconds the tolu ene predominated and we had no knowledge of the other being in there. Mr. Arthur G. Beyer (Research Engi neer, United American Bosch Corporation, Springfield, Mass.): Do I understand you to say that those men who were afflicted are back on the same job? Mr. F. R. Kaimer: They all returned to normal skin health, as I say, and are work ing on the same job. Dr. Cecil K. Drinker: Dr. Schwartz, you have seen a good deal of this general subject. Dr. Louis Schwartz (Medical Director, Dermatoses Investigations, United States Public Health Service, New York, N.Y.): I am primarily interested in dermatitis and it was only because of my researches in that field that I happened to come across infor mation given to me by Dr. Gray that there were some cases of yellow atrophy of the liver attributed to halowax. I can only talk from personal experience about the skin cases. I know from what I have seen and from what I have heard from doctors who have been treating these cases that if they are treated like an ordinary acne vulgaris and kept away from further large exposure they all get well, with the same results as acne vulgaris. Those who have large pus tules may have scars resulting and those who have superficial pustules or only come dones won't have any scars. As far as prevention goes, I felt even be fore this investigation was undertaken that this substance, like any other poisonous substance, can be handled and used in in dustry provided proper safety precautions are taken, and I so advocated at the meeting in Pennsylvania when this was discussed. About ventilation and safety precau tions, I think that while we cannot, with our present knowledge, detect by any chemical tests the early symptoms of intoxication from this substance, the skin offers an easy way of proving whether your method of ventilation is efficient or not. If there are any cases of acne or of this dermatitis occur ring in a plant where halowax or the chlorin ated naphthalene or chlorinated diphenyls are used, then that shows that there is suf ficient concentration of these substances in the air to cause plugging of the follicles and to cause a skin condition. If there is suffi cient concentration to do that there may be vol. 19, no. 7] EFFECTS sufficient concentration to poisoning in the few people sensitive to the action of t bons. Everybody is not hj them. If they were, of th people who have been hand Stances, more would have i disease and it would have very much earlier. This rn; in Germany as early as 19H While I cannot add ar methods outlined here for sa of ventilation and so forth, if you go into a plant and fii any acne present among th this material you will kno' sufficient of the substance in acne and consequently suffic be dangerous to the few ] hypersensitive to its action Dr. Cecil K. Drinker: tical point in regard to the qi mining these substances in a pointed out this morning several pieces of apparatus It has seemed desirable to i men who are here that durii pie of years, while we are learning, that we endeavo confine our analyses to on< ratus, so that at least our r comparable as we can make to place. I don't know much aboi the subject: perhaps, Mr. an idea or two about that. Mr. Warren A. Cook ( Hygienist, Bureau of Oc eases, State of Connecticu Health, Hartford, Conn.), mination of the halowax wouldn't be preferable to perly discuss the method h throughout the country fo tion of chlorinated naphtl Dr. Cecil K. Drinkei as that is concerned it is lb to discussions with Mr. H Brandt afterward. But determining some uniform a while at least is, I think eral interest to us. PLTEXP010361 rOXICOLOGY [Sept. 19$7 lass.): Do I understand you hose men who were afflicted ie same job? . faimer: They all returned to ealth, as I say, and are workle job. K. Drinker: Dr. Schwartz, i a good deal of this general Schwartz (Medical Director, nvestigations, United States Service, New York, N. Y.): r interested in dermatitis and :ause of my researches in that ppened to come across infor- to me by Dr. Gray that there ies of yellow atrophy of the ed to halowax. I can only rnal experience about the skin v from what I have seen and iave heard from doctors who iting these cases that if they ce an ordinary acne vulgaris i from further large exposure ell, with the same results as Those who have large pus /e scars resulting and those rficial pustules or only coins- live any scars. . ivention goes, I felt even be- tigation was undertaken that like any other poisonous i be handled and used in in- ed proper safety precautions Iso advocated at the meeting ia when this was discussed. tilation and safety precau- hat while we cannot, with our idge, detect by any chemical y symptoms of intoxication tance, the skin offers an easy lg whether your method of efficient or not. If there are ne or of this dermatitis occur- where halowax or the chlorin- ine or chlorinated diphenyls that shows that there is suf- ration of these substances m : plugging of the follicles and condition. If there is suffi- ition to do that there may be 1 3 .> . vol. 19, no. 7] 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, more 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 is any acne present among the workers with this material you will know that there is sufficient of the substance in the air to cause acne and consequently sufficient perhaps to be dangerous to the few people who are hypersensitive to its action. Db. Cecil K. Drinker: There is a prac tical point in 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 coniine our analyses to one piece of appa ratus, so that at least our results will be as oomparable as we can make them from place to place. I don't know much about this phase of the subject: perhaps, Mr. Cook, you have an idea or two about that. Mr. 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. Hemperly 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, I 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: Yes, 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 seems 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 306 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. mi 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 fanB which might become loaded with the condensed chlorinated naphthalene, there might be poorer ventilation than origi nally designed and higher concentrations of the chlorinated naphthalene than origi nally determined. It seems to me that it would be an ex tremely desirable thing to have made avail able for all of us who are making these determinations these reference points so that in Massachusetts and in Connecticut, at one plant or at another, a considerable group of workers could be taking samples at this one particular point with reference to the source of generation of the vapor. Such results would permit a comparison of knowl edge between plants. In that regard it happens that there is a committee of the American Public Health Association which is charged with the devel opment of chemical methods for determina tion of atmospheric contamination such as that now under consideration. It seems to me that it might be a very desirable project for that committee to consult with the in vestigator of the Halowax Corporation and suggest to all of those who are doing work of this type, after some discussion, what reference points could be adopted and also what should be done in connection with get ting these average exposures. As a matter of fact our committee will discuss that very feature and possibly include it in our report before the A. P. H. A. in October as one of the projects which we shall carry out at that time. As I have not given this consideration, I am afraid my discussion is not as connected as I might wish it to be. We have a real problem 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 be a splendid idea because we have a bulk of information on this particular material. A number of individuals have given much thought to the development of apparatus, both the combustion method which we have here and also the continuous record type of apparatus which Professor Drinker mentioned this morning. I think that it is a sufficiently important project that a sub-committee made up from this group could give that committee a very definite steer. [Personnel of the Sub-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. Hervey B. Elkins (Chemist, Divi sion of Occupational Hygiene, Massachu setts State Department of Labor and Indus tries, Boston, Mass.): In connection with what Dr. Schwartz has said, I am not sure that I am in complete agreement as regards the use of skin lesions as warning agents. It is my understanding that in insulated wire plants the chlorinated diphenyls are very commonly compounded with the chlo rinated naphthalenes. It is also my under standing that these are more likely to cause a severe skin irritation than the straight chlorinated naphthalenes. On the other vol. 19, no. 7] EFFECT hand, from Dr. Drinker's judge that the straight cfi thalene was nearly as toxii mixture of it with a small rinated diphenyl. In the condenser factor our cases there is no chlor used and no acne of the tj the reports on the insulate^ Dr. R. Emmett Kelly 0 ical Co., St. Louis, Mo.): I anything to the laboratory t has been quite a little hum tion in the last several yea our plants where we have b ing this chlorinated diphen our observation that althoi sion we did have a more i series of skin eruptions whi able to attribute as to caus impurity in the benzene we the chlorinated diphenyl, w any systemic reactions at We have examined them ^ from what laboratory te might help us and from t point. Also from chlor alone there have been no i poisoning reported. I don't believe that we i laboratory results into tb without paying considers the volatility of different si way they are being used. Dr. John A. Hookey matologist, Halowax Corj Mich.): I have had consid with the dermatological a lem. The experience at t at Wyandotte definitely w: tosis did increase when used rather than the str naphthalenes. From the discussion we I think the observation I that the chances are thi problems will disappear al is probably true. Howe certain precautions, certa ures, you might say, sh hiring men who are goi these products, even tho PLTEXP010363 OXICOLOGY [Sept. 1987 . H. A. in October as one of hich we shall carry out at t given this consideration, I iscussion is not as connected i it to be. We have a real uid one that deserves some 1. Drinker: Would it be of merican Public Health Assottee if a sub-committee from collected perhaps by my ise of you involved with these to make a recommendation A. as to the things you have d as to suitable apparatus, al statement come from the er they have considered that h :n A. Cook: I think that endid idea because we have irmation on this particular lumber of individuals have ought to the development of th the combustion method here and also the continuous apparatus which Professor oned this morning. I think ifficiently important project nmittee made up from this ive that committee a very f the Sub-committee: W. A. n, A. L. Coleman, H. B. Elniton, S. W. Gurney, E. R. Hemperly, F. W. Sehl, and d.] r B. Elkins (Chemist, Diviational Hygiene, Massachulartment of Labor and IndusMass.): In connection with artz has said, I am not sure mplete agreement as regards i lesions as warning agents, ^standing that in insulated e chlorinated diphenyls are I compounded with the chloalenes. It is also my underhese are more likely to cause irritation than the straight iphthalenes. On the other m Skiv. vol. 19, no. 7] EFFECTS OF CHLORINATED HYDROCARBONS 307 hand, from Dr. Drinker's work one would judge that the straight chlorinated naph thalene was nearly as toxic at least as the mixture of it with a small 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 had 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 after 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. Mr. F. R. Kaimer: I 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 chloronaphthalene than with the straight chloronaphthalenes. Did you mean by that, that the acne condi tion actually was more pronounced with the compounds than with the straight chloro naphthalene or was that due to the fact that you were in a plant operated in a different fashion? In other words, you handled your numerous wire compounds in more of a batch operation. That is my understand ing from Mr. Brown. Is it a fact that the straight chloronaph thalenes 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 I started working with them the men in the plant said PLTEXP010364 308 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. 19S7 that they developed acne more often and more severely after they started making compounds. It may be that it was in the method of the handling. Mr. F. R. Kaimer: You say that the con dition increases with the increased chlorine content and we are attributing the acne pri marily to the chlorine radical. If that is true, what are we to associate insofar as these various other constituents are con cerned, such as various plasticizing agents? How much do we know about those insofar 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. Hookey: I don't know about these other materials. Perhaps Dr. Schwartz would know something more about them. Dr. Louis Schwartz: It is well known in industry that there are many compounds that cause acne. For instance, paraffin acnes and oil acnes have been known for a long time. Paraffin acnes, 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 Compm,ny 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 glands 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. Royal 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 particles 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 vol. 19, no. 7] EFFECT! jgjjj-iii .... that the condition, whatevc tions might have been, cam cold wire, in a confined I think this needs a great < Dr. Drinker, than you and have been able to give it a: curious about is the way we the protective labor laws in both the employer and the e I listened with very greai expositions of suggested po cation of halowax, chlorina' and diphenyl. It seemed 1 left very much to be desiri why the application of th< pound, if it is necessary, as to use this rather dangerous i be done in a practically clof please, Dr. Drinker, I wish Mr. Reeves of the Rockb Corporation to tell how the . it. If I am any judge of safety devices they have c eliminating entirely from " all contamination from fum rated halowax as anyone. cation of halowax, either in or where it is applied to tl under hooding and with v< ratus, and it seems to be en Mr. B. H. Reeves (Vic General Manager, Rockb Corporation, New Haven, ( very glad to tell of our exp help the picture along. Or been more or less parallel w in as much as we manufactu of wire. We have avoided ture that he ran into, pro) v fact that shortly after 192 benzene as a solvent for asp We got into anemia difft zene fumes and had to in ventilating system to re fumes from the machines compounds to the wire, installation of that equipir out of the picture. We are still in the same else is as far as finding a su wax. There is none that w sequently when we went ti PLTEXP010365 OXICOLOGY [Sept. 1987 apt to occur. The sebacelost active and they seem to ore than the older people in iceous glands are not so pping of all articles relating umatitis in my office and I 1 article in a German magathey report in Germany a ondition from chlorinated orinated benzenes and solid is that this acne-like condiiliar to halowax or chlorinnes or diphenyls but can condition that blocks up the les of the skin. Meeker (Special Agent, iticut Department of Labor, i.): I am full of questions, l I am a little bit suspicious should think that we should i well as averages in getting 1 dose or the dangerous imthe atmosphere with these pounds. I just wanted to hint for this committee to work. vhat you said at luncheon, itill think it is rather imporine how the plugging of the loes occur, whether they are . Schwartz has suggested, les falling on the outside of ther they are plugged, as so ive informed me, from inside he fumes are breathed, the into the blood stream. It is rgh the pores of the skin and lugged. I think it is rather determine that because it .m the slight knowledge that dustrial application of halo s in insulating wires, that the skin, if it is just an outnay take place either from id substance or from the wire after it becomes cold, ard anybody say anything assachusetts cases of very is and I am not so sure but some question of liver damody has said anything about There is no question there vol. 19, no. 7] EFFECTS OF CHLORINATED HYDROCARBONS 309 that the condition, whatever the complica tions might have been, came from handling cold wire, in a confined area of course. I think this needs a great deal more study, Dr. Drinker, than you and your associates have been able to give it as yet. All I am curious about is the way we can administer the protective labor laws in order to protect both the employer and the employee. I listened with very great interest to the expositions of suggested pots for the appli cation of halowax, chlorinated naphthalene and diphenyl. It seemed to me that they left very much to be desired. I don't see why the application of the halowax com pound, if it is necessary, as I assume it is, to Use this rather dangerous substance, can't be done in a practically closed pot. If you please, Dr. Drinker, I wish you would ask Mr. Reeves of the Roekbestos Products Corporation to tell how they have handled it. If I am any judge of equipment and safety devices they have come as near to eliminating entirely from the atmosphere all contamination from fumigated or evapo rated halowax as anyone. All of the appli cation of halowax, either in the melting pots or where it is applied to the wire, is done under hooding and with ventilating appa ratus, and it seems to be entirely adequate. wax we had a head start as far as 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 same scheme of applying the compounds and used a completely enclosed pot. There is a hole in one side for the wire to go in and one on the other side for the wire to come out. There is enough exhaust suction on the enclosure to prevent any fumes from getting out of the openings where the wire enters and leaves. Of course periodically it is necessary to open the pot to replenish the compound or make adjust ments. In that case we have the ventilat ing system interlocked with the door that the operator opens so that when he opens it he increases the amount of air travel about ten-fold. Dr. Royal Meeker: What is the veloc ity when the door is open? .* Mb. B. H. Reeves (Vice-president and Mr. B. H. Reeves: With the door wide General Manager, Roekbestos Products open, at breathing level the velocity is 200 Corporation, New Haven, Conn.): I will be feet. That is the linear velocity. We very glad to tell of our experience if it will check that every week on every opening at help the picture along. Our experience has every machine with a velometer, a small been more or less parallel with Mr. Kaimer's instrument which is easy enough to operate in as much as we manufacture the same type and reads directly. Whenever the velocity of wire. We have avoided the serious pic falls below that figure the pipe connecting ture that he ran into, probably due to the that machine is taken down and cleaned, fact that shortly after 1923 we were using because there will be condensation inside benzene as a solvent for asphaltic materials. the pipe to cut down the air flow and reduce We got into anemia difficulties with ben the ventilation efficiency. zene fumes and had to install a complete ventilating system to remove all those Dr. Royal Meeker: What do you think fumes from the machines that applied the of that trap device shown? compounds to the wire. Following the installation of that equipment we were able Mr. B. H. Reeves : I don't know what to to get a substitute for benzene, so we got it think of that. I don't know whether it out of the picture. would be practical or not. I was going to m We are still in the same fix as every one ask Dr. Drinker whether in passing the air else is as far as finding a substitute for halo laden with halowax fumes through the boxes wax. There is none that we know of. Con of rats there was any deposit of halowax in sequently when we went to the use of halo the enclosure. PLTEXP010366 310 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. 1937 Dr. Cecil K. Drinker: Yes. It is detectable readily through the outflow pipe. Mr. B. H. Reeves: Those in the far end probably didn't get the concentration. Dr. Cecil K. Drinker: We change the position of the boxes each day. The ones furthest away move into the nearest posi 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. Emery R. Hayhurst (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. Vosburgh (Medical Director, General Electric Company, Schenectady, New York): We have heard about the pos sibility of preventing liver damage and skin 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 so 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. Vosburgh: I did write down a few questions that came to mind. Some of them have been answered and some are foolish but I shall ask them anyhow. It occurred to me that if trichlornaphthalene 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 as yet. Dr. 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 rats before they ran out of lesions. We don't know how long it lasts. Dr. B. L. Vosburgh: 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. < ' "j ' " ''' ,, i' vol. 19, no. 7] EFFECT! Dr. B. L. Vosburgh: I questions in mind. I woe what Mr. Brown would say bility of using only this chlorinated naphthalene. Mr. Sandford Brow: simplify our problem excee from the commercial stanc the toxicity standpoint. I I think that Mr. Kaimer w to object because he wouldi the technical effects he desi The same thing applies th: industry where we are usi chlorinated products. The problem as we see which we intend to study i our program for this contii will be done under the < Drinker brothers), is to trj demarcation and whether o complicated chemical str some one thing that causes we could take hexachlorr remove l per cent of some i Uet with which we are i and eliminate the toxicitj a lovely solution. Whethe able to attain that I don't one of the things we have i As I said before, that is with which all manufactur thetic organic products a some stage, either in their 1 commercial developments, question of timing as to wh the work, how much you whether you know how to to learn that first. Dr. Cecil K. Drinker some other important mat the meeting adjourned. Dr. R. R. Sayers: M more with regard to what I on syphilis? If you are g all your workers who lit PLTEXP010367 TOXICOLOGY [Sepf. 1937 ere bona fide. We had no difndling cold wire and the men trouble. Yet when they did g with possibly the application mels, ships and so forth, they develop trouble. ied, of course, the icterus index )me carbon tetrachloride cases id what you have to say about . of no value at all in the case ge in this material? K. Drinker: I don't think so ) extreme that we know it any 'osburgh: I did write down a that came to mind. Some of sen answered and some are shall ask them anyhow. to me that if trichlornapbeen proved to be practically 1't it a problem of research : Halowax Corporation to use material adopted with other ated compounds to meet the of customers? That is one ones probably, but I shall e, how long is it reasonable to <t to recover after it has been maged. I talked to you and ladn't worked that out with yet. , : C. Drinker: In that case we rtain number of animals to knowing that a certain nage had been done. Then kill them but we invariably oefore they ran out of lesions. ' how long it lasts. t'osnurgii: Have you given nd glucose as you would with loride? . Drinker: Not yet, but we periment now with one group 1 calcium diet and another eium free diet. The whole cium in the diet, of giving these people may be worth tol. 19, n0- EFFECTS OF CHLORINATED HYDROCARBONS 311 Dn. B. L. Vosburgh: I just had those questions in mind. I would like to hear what Mr. Brown would say as to the possi bility of using only this one innocuous chlorinated naphthalene. Mr. Sandford 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 gome one thing that causes the trouble. If we could take hexachlornaphthalene and remove 1 per cent of some unknown constitueat with which we are 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 synthetie 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. Dh. Cecil K. Drinker: Unless there is some other important matter I will declare the meeting adjourned. Dr. R. R. Sayers: 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 wre 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. PLTEXP010368