Document pepw752X25ykVw22baYpJm5yD

THE JOURNAL OF INDUSTRIAL HYGIENE (AND TOXICOLOGY) VOLUME 19 JANUARY, 1937--DECEMBER, 1937 PUBLISHED BY . THE WILLIAMS & WILKINS COMPANY Baltimore, M d. " C1B 34977S THE JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY 3y5*- *y.Vv Volums 19 SEPTEM BER, 1937 Numbxb 7 THE PROBLEM OF POSSIBLE SYSTEM IC EFFECTS FROM CERTAIN CHLORINATED HYDROCARBONS* Cecil E . Drinxeb, Madeleine F ield Wa&ren and Granville A* Bennett Departwuni of Physiology, Harvard School of Public Health and Department of Pathology, Harvard Medical School, Boeton, Mata. THE use of chlorinated naphtha lenes and compounds of allied pharmacological possibilities is extremely wide, and w ith the steady growth of the use of electricity is cer tain to expand much farther. For yean 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 qrstemic effects following ingestion or inhalation of such products. In the spring of 1936, the Halowax Corpora tion, a division of the Bakelite Cor poration, called our attention to three fiiial eases of jaundice in workmen _ chlorinated naphthalenes and {ckfocinated diphenyl, and requested , A o t the subject be investigated as gf * Beeehred for publication June SO, 1037. rapidly and thoroughly as possible-t In brief these cases were as follows: Patient t. Male, age 21. The prerious medical history of this man was in no way significant except for the feet that he had an attaek of jaundice about 6 weeks prior to bis fatal illness. Late in December, 1236, be became badly constipated and had much abdominal pain and distention. When ad mitted to the hoepital he was slightly jaun diced and was eridently eery ill. He was somewhat anemic and his skin, particularly upon the arms, face, chest and back, showed many pustules. He died after a brief period in the hospital, and at autopsy was found to t The Halowax Company makes many products besides chlorinated naphthalenes, and it has come to our knowledge that all of these produets are indiscriminately called "halowaxee" by purchasers and users, and are lumped together as possible causers ef acne and even of systemic disease. Sines "halowax" is merely a trade designation, care should be taken to describe compounds by their chemical names and thus iro id condemnatiooa which are both trouble and miilesdmg. I m . -% i; u 5r: 3 -'it i-1 m s irM Q to to oo h 284 JOURNAL OP INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. 19S7 have a cirrhosis of the liver with acute yel low atrophy euperimpoeed upon it. This man bad been erpoeed to low concentrations of vapor arising from a mixture of tetra and pentachlornaphthalenea, together with approximately 10 per eent of a refined chlo rinated diphenyl. While both he and other engaged in the same work had ehloracne, there were no other disturbance of health in fellow workmen, nor was there any pre cipitating cause for the acute yellow atro who had been exposed to trichlornaphthalene. Of these 13 were found to have mild digestive com plaints, anorexia, nausea and vertigo, but 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 phy such as treatment with arsphenamine or exposure to dangerous concentrations of carbon tetrachloride. Patient t. This was a young man who died in February, 1930, after an acute illness characterised by jaundice. He had been to be of little consequence considering the mildness of the digestive troubles and the absence of respiratory phe nom ena." In Touraine's cases the exposure was exposed to fumes arising from a mixture of penta and bexacblornaphthalenea. There is no record of ehloracne. 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 chlorination. Our own experiments indicate that trichlomaphthalencs re Patients. Another young man employed with Patient 3. He became jaundiced in March, 1936, and died after an illneaa of 2 weeks. A careful autopsy resulted in a diagnosis of acute yellow atrophy of the liver Here again no history eould be ob quire enormous dosage, far beyond anything encountered in industry, in order to produce liver damage. Teleky (1927) reported a number of cases of ehloracne in persona 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. H e found that the lower the In addition to these three very re chlorine content the leas th e acne. cent fatalities, we have learned of four Mittelst&dt (1935) examined a number other possible cases, none of them of cases of ehloracne 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 th e nature of serious disease. Re- out of large groups having the same girding his *mm*l experimentation, exposure. In but one instance, P a 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 tim e and that, health of fellow workers has been good. whether poisoned by inhalation or by 8uch 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 tem ic 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: 737137 prf. IP, no. 7| EFFECTS OF CHLORINATED HYDROCARBONS 285 L A mixture of tri and tetrachlornaphthalene. 2. A mixture of tetra and pentachlom aphthalene. 3. A mixture of penta and hexachlornaphthalene. In addition, sublimated 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.1' 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 m men working with chlorinated naph thalenes but give no details in regard to them. These cases are undoubtedly the same as those described in the beginning of this paper. Cne may summarise the meagre literature upon system ic effects from th e* 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. T he amounts reaching the air under such circumstances are hardly detectable. It will however be shown th at 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 286 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY |*SVpr /.q; 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 w ry similar to man, and in the case of th>c chlorinated compounds it is that diet may be very significant. Finally, their normal characteri>rirs have been described so well as to muk< the detection of abnormalities Uth easy and certain. Method of exposure.--The inhalation experiments were carried out in four large air-tight wooden boxes, w U capable of holding ten rat cages, -i*. 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.--W hite rata 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 tr. cages each. When the experiment w i> 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 of. 19, no. 7 ing the on `meter was the flow of could be ad from a ca deflector pi pipe into tl sure a un: stream of a At the op outflow em was exhaus fitted with ; a large cem About 4 i the 7-inch p of '{the subi duced into cially des\[ (figure 4), 1 diameter of hold the he were made that extend top of the fi "this fitted 2 length. Th 1Into a large tightly into t ' pipe on the \ flask in tum heater mad* - below the si top. Rubb* aide arm a it voir and a g through the motion and Into each flat ' centigrade t ,ie p t in place time above which it past Approxmu PO*. 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 tier 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), 7} 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 1$ inches in length. This short tube was inserted into a large rubber stopper that fitted tightly into a hole cut out of the 7-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 aide 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 gra. 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. alwayB 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 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sep/. 1937 amount in a cubic meter of air per minute as determined by a series of Fio. 3. Outflow end of two boxes showing connections to exhaust system. . / :V . St Fig. 4. Pyrex glass flask flowmeter readings. The figures ob 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 checked well with direct determinations through air sam ples. 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 w*as made to keep the four boxes as 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 trichlorn&phthalenes plus a trace of tetrachlornapthalene. Chlorine content 49.9 per cent. 2. , mixture of penta and hexachlomaphthalenes. Chlorine content 62.6 per cent. 3. . 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 in each cage. They were fed Purina 737141 oJ. 19, no. 7] Dog Chow s eggs, milk an This first g begun on Ju. exposure tom chlornaphthal 16th. Thee? compounds c 18th. On 0 tive animal ' sure from groi `-k illed after 2 15th, in order Conditions Mxi Trichlornaphthai tetrachlomaph TT\ \ Penta and hexac. 90% penta and Jenes plus 10% c Chlorinated diph : period would b the affected 1 group 3 were a .exposure on <> ?fOT w xm inafiftq The average 1 l6 hours daily i morning a 'ceased, and be : 4:00 p.m. the_i weighed, etc. Wbrmity shifted o m 2 1 ooto VO t ~ n EFFECT8 OF CHLORINATED HYDROCARBONS jjog Chow supplemented by lettuce, milk and cod liver oiL Ib is first group of experiments was 'begun on July 1, 1936 and the last mcpoeure to number 2 (pent* and hexeblomaphthalenes) was on November 16th. The exposure to the other three compounds ceased upon November 18th. On October 15th represent tin f.n<th 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. A t dif ferent tim es during the course of the experiment tests for free chloride were made but were uniformly negative and TABLE 1 7 C o m m o n Maintain in Inhalation Expcanairr raoH J olt I to Novxunia 16 and 18 V 1-&S^ '; v. K iT O U fc CiSnXAi CO W TBJTf or AIA(XoxA T , e O K i n t A T I O R mmxox>aia BAATJL. T imX*a SL.'ni % c. a rm#8 W Wwv ^ TrtiloniJtphtlijJene plus trace* of Vi' UiracHomaphthaJcne................... * a'i1* Me- and hezaehloroaphthalenet.... 40.9 83.6 150-160 1.31 High 3 60 Low 0.10 160-170 1.16 High 3.19 Low 0.51 1896 1864 16 16 >vlP% penta and hezaekJomaphtha- s knetpiuBlO%eklornateddiphen]rl. 63.0 yy.'- ^CHorinated diphenjl.'....................... 65.0 tV 165-175 1.57 High 3.17 Low 0.64 166-175 0 57 High 119 Low 0.38 1896 1896 16 16 ^period would bring about recovery in affected liven . Animals from rgjeup 3 were similarly removed from ^exposure on October 4th and killed fexamination on December 4th. t i n average length of exposure was y & io u r s daily for 8 days a week. "i morning at about 9:00 exposure jd^ and between this tim e and p ta. the rata were cleaned, fed, etc. In order to secure uniof exposure 'the cages were on a regular schedule, since showed th a t under the temperatures used no decomposition occurred. Table 1 shows the temperatures at which th e various substances were held, the average concentrations per eubic m eter of air, and the average expoeuree from July 1 to November 16 and 18. The concentration of chlorinated naph thalene* and chlorinated diphenyl m (he asr of workroom*.--Table 1 shows that animals have been exposed to varied concentrations of the substances under f1 *~ iV J. :P ,i.r r m w^ .-.7V7 ill 737142 290 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sep*. 937 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 estim ates of chlo rinated hydrocarbons in the air of dif ferent factories were made and the 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- socnoM prrncntx. iMdiDcoun -4OU0 OIAS3S*AO9 tnn oiah. NOTOCAttNTOCAL* saroi aa-M cn. ac*. T #T niiiiMtoe vut pot* TIP IMMC* FCIMo *ontn/rmfiv suTiMun m vm cxtP c 7 noior IS.4 &0 I * CL.OOS4 C n . Fio. 6. DimensioMd sketch of eoabuatioa tube ta d absorption apparatus. concentrations chosen for inhalation experiments depended on these exami nations. The technic of analysis end the apparatus employed were the work o f Frederick R . M illhiser and William F . Hemperly. H e method and apparatus used for determining concentrations of chlorin ated hydrocarbons in air were adapted from well-known procedures. H ie air mined nepbelometrically 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. H ie absorption tube is *. 1, 0. *1 % somewhat east if/' Tebbens'sb u t devices are tb In both ca* rinated hydro acid and sul sodium carboi In our case c apt to be vej less than 1 m quently the a actually fonrn E * so small that itEer gravim i For this reaso use the nephe is sensitive t i"rv as 0.1 mgm. p - It is doubt |3s- should exceei renioa o : subsequ1e0n,t baJi iadess the ve! low. Anothi that the c any cblorim determined. '"A ' dwtingtit.li t> r butdet suits i puted in ter v ` At the pr formation a* rinated napl different pis Instances th< ..repeated ae .Jhe amount 737143 EFFECTS OF CHLORINATED HYDROCARBONS 291 p% :<i-/. '^ so m ew h a t 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 add sad subsequent absorption as "&&&. carbonate should be complete, la our concentrations in air are apt to be very low--the objective is fem 1 mgm- per cu. m. Conse 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 tim e that the concentra tions of chlorinated hydrocarbons used in our experiments would be dangerous for workers in the case of compounds quently the amount of silver chloride above trichlomaphthalene in chlorina actually formed in the final reaction is tion. Fortunately it is easy to venti "*1% - i? **"*** that H can not be determined late processes of manufacture which ether gravimetrically or by titration. require these substances and to reduce Tor this reason we have been forced to air contam ination practically to the use the nephelometric procedure which vanishing point. Such treatment of is sensitive to concentrations as low the problem at once removes both the > 0-1 olg a . per cu. m. of air. |tCSrSf-BT-fi-lWfeY.-. It is doubtful if the sampling rate r ^ 5 ribouid exceed 1 liter per minute as conversion of the chlorinated com_vg^y pound to hydrochloric acid and its possibility of system ic poisoning and the annoyances that arise from cases of acne. Result* of Inhalation Experiment. flbfassquant absorption are not efficient 1. Animals exposed to a mixture l.- .jss^r voloaty of the gas stream is of trichlornaphthalenes plus small Another precaution to be noted am ounts of tetrachlomapthalene. that the method is not selective-- Living were apparently en Mpr ribtwinsted substance will be tirely normaL Autopsies performed j& tfcnniried.' Furthermore it does not near the end o f exposure seemed to ^.jnsfinguah between solid particles and show slight- swelling of the liver, and (R es but determines them all alike and microscopic examination occasionally t f s results must, of course, be comFfrtcd in terms of total chlorine. 0 M the present time we possess in formation as to the amounts of chioffirted naphthalene* in the air of 30 showed swollen and hypergranular liver cells. The changes were, however, never more than alight. 2. Animals exposed to a mixture of penta and hexachiornaphthalenea. and in a number of N o abnormalities were observed in the the measurements have been living animal* Rata were killed and times. Frequently autopsied every 6 weeks. In the first been greater than animals sacrificed liver changes were % our experiments, but H i i&it - 7 "" bered th at th e rate ihwrtiiu ad absorption appa> t to iold sampling is now a id * Prndueb, Ine., Reading, Pa. - . * n t jpeladw flowmeter sad p nnp with a carrying caee. observed. Theae were swelling of cells, alight granulation and hyalinixation. In September and October these conditions were somewhat more ad vanced, and in November the process became stationary. There were highly J 737144 ; i% I'd 292 JOURNAL OP INDUSTRIAL HYGIENE AND TOXICOLOGY IS?*. 1937 granular cells, hyaline inclusions and m itotic 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 m itotic figures. Hyalinization was always present as a result of inhalation of chlorinated diphenyL Summary of the first inhalation ex* perimeni.--In these experiments care ful observation of appearance, body weight, activity, blood, and urine showed no abnormalities of any sort. Y et after 6 weeks' exposure all the compounds with chlorination above trichlomaphthalene 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 alight 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 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 dncophen. 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 th is now and then does happen to pa tients under antisyphilitic treatm ent. 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 fiver changes such as existed in our rats, changes not recognisable through 737145 *1.19, no. 71 ] say means othe: [i. nation. If, upc such changes, tl disturbance, acu not a very com which any of us t this relatively i over to acute ye * Knowing that had liver ehang slight to cause re we decided to t* substances know structhm. Carb alcohol were self mation that 1.0 hlorids plus 1.0 v per kilogram woi normal white raU ... to 0.75 cc. carb cc. of ethyl |jsi -T h is mixture a ^$*2^tufce to the folic suds and with th JpQowmg tabulat 0.7t ee. p ^ UtncUorids a EfeySSSsTt j ** Mtom v friM om apkik MtanmpkthaUns. 1 18. 10 rats. Pm ia and ksxa 8 :3 0 ijn .f Nor. 1 I died Nor. 1 *10:30 p.m. -V s 1 died Not. 12t *Y.-\ 1 died Not. 12tl died Nor. 1 ,c*y . 11:90 u s . 1*1 died Not. 16th ^ 14* ood 12 Mi/. died Not. li Not- Uth isndlO perct 1st 10:00 s a ., I Q m 2 oo K> U> v -^1 m if, -- *1 EFFECTS OF CHLORINATED HYDROCARBONS 293 gg*/' 'ja y means other than autopsy examiv "s naty^ If. upon the substratum of uch changes, they got an acute liver disturbance, acute catarrhal jaundice, got a very common disease but one which any of us may experience, would th e relatively innocuous disease go over to acute yellow atrophy? Knowing that our inhalation rats had liver changes, but changes too rfght to cause recognizable symptoms, we decided to test their resistance to known to cause liver de struction. Carbon tetrachloride and . - alcohol were selected. Having inforf.<. station that 1.0 cc. of carbon tetra- chloride plus 1.0 cc. of ethyl alcohol l&V' per kilogram would kill 14 per cent of normal white rats, we reduced the dose `to 0.75 cc. carbon tetrachloride and 0.75 ee. of ethyl alcohoL >r This mixture was given by stomach tube to the following groups of animale and with the results found in the following tabulation. 0,1$ ee, per bpm, each of ea tetrachloride and ethyl alcohol bp #yKi-\ oUmaek tuba TricUonaphlhaUns plue trace of idra* jcUornapkthalene. Fed i i 9:00 aja., Nov. 10rets. No deaths. - I Fonia and hesacklornaphihaUneo. Fed a t t : i a . f Not. 10,1935. 10 rete. 1 died Nor. 11th between 4:J0 end . 10:30 p ju 1 ^ ; 1 ditd Not. 13th at 3:30 p .a. 1 4 M Nov. 13th a t : p a . h ,l 4M Nov. Utk botvooa : and U :D (a .i 1 dM Xov. Utk botwooc night of Nov. } Mth and : pjn. Nov. Uth. 3 teK M Nov. Uthbotwooa 10:15 p a . 1;,,Nov. 15th'sad 0:00 a a t. Nov. and pania and hexachlomaph and tOpar coni chlorinated diphenyL 5* 15:00 aj*., Nor. 10 1916. 10 rate. 1 died Nor. 10th between 5:00 end 10:30 p.m. 5 died N ot. Uth between 4:30 end 10:30 p.m. 1 died Nov. Uth between 4:30 p.m. end 9:00 e.m. Not. 12th. 2 died N ot. 12th ebout 1:00 e.m. 1 died Not. 13th between 5:00 end 10:00 p.m. 4. Chlorinated diphenyl. Fed e t 10:00 e.m .f N ot. 10,1930. 10 rete. 1 killed N ot. 10th et 10:30 p.m. (elmoet deed). 2 died Not. Uth between 4:30 end 10:30 p.m. 1 died Not. 12th before 8:30 e.m. (stiff). 1 died Not. 13th between 9:30 end 11:00 e.m. 1 died Not. 16th between 10:15 p.m. N ot. 15th end 9:00 e.m. N ot. 16th (stiff). Control: Fed et 9:30 e.m., Not. 12,1935. 10 rets. 1 killed Not. 13th for normel liver. Thin tabulation summarises into the facte that: 1. No normal rata were killed by carbon tetrachloride and ethyl alcohol. 2. N o trichlomaphth&lene exposed rata were killed, and this finding agrees w ith our inability to find lesions of moment in the liv en of the animals that inhaled this substance. 3. The penta and hexachlorinated naphthalene, the mixture of these w ith 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 Ever function was acute yellow atrophy usually accompanied by jaundice. T his 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. '; M i '' life -* , 737146 II ap \ - m fit-if m V* JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY 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 tetrachlom aphthalene being practically normal on removal from exposure need no consideration. In the case of the penta and hexachlor- signs of liver injury will be many months in returning to normal. The effect of high concentrations of trichlornaphthalenes with traces of telrachlornaphthalene.--The first group of inhalation experiments showed that this material in concentrations averag ing 1.31 mgm. per cu. m. of air was relatively innocuous, judged both by direct observation and by the carbon tetrachloride test. This is an in teresting fact since such compounds cause acne, though less potently than substances of higher chlorination. In order to explore the m atter further one of the inhalation boxes was arranged TABLE 3 Conditions Maintains dubino Inhalation or Hioa Concsmtsations or TlUCHLOSNAfHTHALXNX FLOS TSTSACHLOENAFHTKALaXB K A TSUAb orA T . C O M C B i m L t n O X AXB O f B O X sxrotvuT O T A L IX T 0 6 7 U A T. BAXLT c. \ M#m./.ak Wfi k tn kmmn Trichlornaphthalese plus trace of 137-2001 10.97 High 16 49 1232 16 tetrachlorniphthalene Low 5 78 naphthalene, rats after 2 months' re moval from exposure still showed swollen liver cells, increased granu larity, hyalinization and m itotic fig ures. The condition was not advanced as compared w ith rats killed at the tim e of removal from exposure but on the other hand 2 m onths were insuffi cient for recovery. The same findings were true of the mixture of penta and hexachlormated 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 m ust expect that an individual showing any so that fumes from four glass contain ers were delivered to the air line instead of one. This resulted in the conditions shown in table 2. The animals sub jected to these conditions showed no clinical effects of any sort. After 1 month the liver cells were slightly swollen and over-granular and there were occasional m itotic 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 *,es.T l EFT k others this did n> rats were used in tt one may conclude t ebfornaphthalenes a tone as those of h they are not entirel upon the liver if hi| (rations are inhaled The effects of hig penta and hexac There can be no do age done the liver b but in the concen ported no sympton could be; recognij approach I 4ftC- kHar"aoN Maiktai sad hexachlor atrophy occurred ''use of the carbor v^i)a December 1, Subjected to tb feariacd in table p n a terminated or .'`tt animals lost f in d deaths began Fifty-five heavfiy jam 'm icroscopic b y the carl fi ln ed thr jpposnm . The 1 for murrin degenerati w ith necrosis of l sh ow ed ; ^ jSL*i#, no. 7\ EFFECTS OF CHLORINATED HYDROCARBONS ft others this did not develop. Fifty n to were used in this experiment and P- one may conclude that while the trichlomaphthalenes 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 effect* of high concentration* of penta and hexachlornaphthalene#.-- 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 recognised clinically and nothing approaching acute yellow the liver after 35 days of freedom from inhalation. It is thus evident that penta and hexachlornaphth&lenes are markedly toxic compounds and that recovery from their effects is extremely slow . The effect* of penta and hezachlornaphthalene*9 the mixture of these with 10 per cent chlorinated diphenyl, and of chlorinated diphenyl alone, when inhaled in low concentration* through an 8-hour day instead of a 16-hour day a* 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 b^ Q u--p' m oxi Maintained dubing Inhalation or High Concsnteations or Penta and ',,'V Hexachlornaphthalene f'Vr, . . MATSU h l. A T . COMOfTlATIOV o r Aim o r s o x TOTAh AT. SAJB.Y IXPQSCU c . h a t * a n d h e x m c h J o r n m p h t h m l e n e t ............. 1 3 7 - 1 3 5 8 .8 8 H ig h 1 4 .0 L ow 5 .7 5 W 608 Wt 16 trophy occurred except through the -use of the carbon tetrachloride test. ,0 b December 1, 1936, 80 rata were fy objected to the conditions sum^.insriaed in table 3. T his experment i terminated on January 21. All of th e lost weight and appetite j|and deaths began after 8 days of expo- s. Fifty-five rats died, most of n heavily jaundiced, 8 were killed , microscopic exam ination, 9 were l M ed by the earbon tetrachloride test * 8 lived through the period of The liv e n of the animals 1fotr exam ination showed marked degeneration, central in type [necrosis of liver cells. Surviving i 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 rata were used for each of the three compounds tested. N one a t any time showed the slightest evidence of illness. Microscopie ex amination beginning after 6 weeks' exposure showed swollen liver cells, excess granulation, hyaline inclusions and occasional m itotic figures. These changes did not progress and were very similar to those in the animals exposed few 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 eon- . FI i m if *: 737148 Ifc JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. tS V 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 tfaie 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 experiment. 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. Grot Feeding Experiment The various compounds used were ground as finely as possible and mixed with a standard balanced ration for TABLE 4 Conditions Maintainxd Duanra Inkauion o r Low Concxntnations o r T u t u Confounds dusino 8-Hoc* Inbtbad o r 16-Hou* Pxbiods K A n m u ii fIMV. AT. C O H C B N T K A Y S O V or AX SO I B O S TOTAL a t . d a il y sx ro A o m s s z r a c B S c. mf./rm, W L. Am W i Peats sad hexschlornsphthaleaea....... HP-183 1.44 High 2.58 020 8 Low 0.42 00% pent* sad hexsehlornspbihsleaet plus 10% chlorinated diphenyl.......... 150-107 1.66 High 3.30 012 8 Chloriaated dipheayL........................... 156-174 0.08 Low 0.56 High 3.21 Low 0.0 000 8 cate that compounds more highly chlorinated than trichlomaphtbalene 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. I t is not easy to grade the toxicity of the different compound tested, but the chlorinated diphenyl is certainly capable of doing h a m in very low concentrations and is probably the m ost dangerous. Industrial experi ence combined with these experiments make H appear probable that work the white rat. The food was placed in a single container, a t which the 10 animals in a cage had an equal chance, the amount of the compounds added being reduced as the number of rata 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 a te or sites of damage. The experiments were successful in both respects, and indeed one may anticipate that future appraisals of the possible toxicity of chlorinated hydro- If . ft* tot. IP, no. 7] * EFFE carbons may often b< feeding and do not r rate apparatus and ti sary for inhalation e; essential reason for th in the identity of the by both methods, anc different compounds seem to arrange them so far as toxicity is ever way they are a< Trichlornaphlhaleru teirachlomaphthalene. on M ay 4, 1936 until November 2 ,19c ning 3 gm. of this m l -to the food for 10 and this concentratioi ; throughout the expe ^.anim als were killed *Vhich died on N ov. 5 : lo6i of weight and r j illness of any death was due to soi In spiratory infection wl tion to the material i. i Histological exam % slight changes in the ^*bt great significance. 7 Tetra and penlachl Feeding began on J i ^'dosage of 0.5 gm. daii 'All the animals sicker twere either killed or ,4 9 ,1 9 3 6 . At autopsy both g ^logically the liver wat j^jiffected. The liver hypergranulatioi sfdna and vacuolat f ithere necrotic cells we 'WU * tremendous wee *?;Peata and hexaehl reeding began M ay C ) d. 737149 m*. i9, no. 7J * 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 them selves identically so far as toxicity is concerned whichi . . ever way they are administered. Trichlomaphthalene plvo (races of tetrachlomaphthalene.--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 N ov. 2. There was no loss of weight and no appearance of wasting illness of any sort. The single death was due to some variety of re spiratory infection which had no rela tion to the material inhaled. Histological examination showed slight changes in the liver but nothing of great significance. Tetra and pentachlornaphlhalenet.-- 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 . - , 29,1938. At autopsy both grossly and histologically the liver was the single organ ^ - affected. The liver cells showed swell~ ing, hypergranulation, hyaline indu^ v boos and vacuolation. Here and : t h e r e necrotic cells were found. There -gvV.-^-W ta a tremendous accumulation of fat. Penta and hexachlomaphthalenet,-- ' ^.-.^x Feeding began M ay 4, 1936, a 3 gm. -X ^vJ?" Se being used. B y June 6, nine rats had died. The last one was obvi ously ill and was killed for autopsy examination. All animals lost weight from the beginning and were ill. At autopsy the liver alone was affected, the lesions observed being similar to those that have been described for tetra and pentachlomaphthalenes but worse. 90 per cent penia and hexachlornaphthalenet and 10 per cent chlorinated diphenyl--Feeding began M ay 4, 1936 on a 3 gm. dosage. On M ay 16th feeding was stopped but all the animals went on to death, the last dying on June 8th. An autopsy the liver lesions were extremely severe and of the usual type. On account of the high toxicity of the 3 gm. dosage, four rats were given a 0.5 gm. dose every other day. Feed ing began June 24, 1936 and the last animal was killed Sept. 11th. There were no deaths but all the animals lost weight. At autopsy the liver as usual was the single organ affected, the lesions being characteristic and ex tensive. Chlorinated diphenyl--Feeding be gan May 4, 1936 on a 3 gm. dosage and was discontinued on M ay 10th. Seven of the 10 rats were dead by M ay 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 M ay 20,' 1936. The first rat died on M ay 29th and four more before June 24th. The remaining were sacrificed. Those rats that died showed losses in weight, while those sacrificed had recovered 298 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Seni. i57 their, initial loss in weight and were and rabbits, the dosage being calcu gaining. The liver lesions were similar lated on the basis of 4 mgm. per cu. m. to those found in rats fed penta and of air. Again similar results were hexachlornaphthalenes plus 10 per obtained. In all such experiments cent chlorinated diphenyl but not so there must of necessity be differences marked. in the degree of effect but invariably Summary of groat feeding experi ments.--Of the various materials fed rats in large doses trichlomaphthalene the liver was the sole organ affected and the lesions were those already described many tim es. plus traces of tetrachlomaphthalene D iscussion was quite innocuous. Tetra and pentachlornaphthalene showed definite liver damage. Penta and hexachlornaphthalenes caused a similar grade of injury. The addition of chlorinated diphenyl to penta and hexachlomaphthalenes increased the toxicity. Chlo rinated diphenyl alone produced liver lesions but in the dosage used was less effective than when mixed with highly chlorinated naphthalenes. In no case did the compounds used produce acute yellow atrophy but the lesions ob served indicate this might be possible if one found a dosage which could act for the proper period of tim e. These experiments leave no doubt as to the possibility of system ic effects from the chlorinated naphthalenes and chlorinated diphenyl. As in the case of the effects upon the skin, the degree of chlorination seems to determine the system ic toxicity, and it is a striking thing that when trichlomaphthalene is reached system ic effects are never marked and are produced with the greatest difficulty. It is most remark able, too, that all the compounds tested attack the liver and the liver alone. During the past few months we have ' determined the organically combined chloride in the livers of ani Feeding Precise Doses by Stomach Tube The compounds employed were sus pended in gum acacia. In figuring the -dosage the total amount a man of 50 kg. would inhale in an 8-hour day assuming an air concentration of 20 mgm. per cu. m. was first calculated and reduced to milligrams per kilo gram. The rats and rabbits received this dose each day. The compounds used were those employed in the gross feeding experiments and the results were essentially similar though the lesions were leas severe. Subcutaneous Infections mals very severely poisoned by penta and hexachlornaphthalenes but have found no increase over normal figures, though the livers, as determined histo logically, were very severely affected. A t the present tm e we are conducting inhalation experiments on' a chlorin ated diphenyl containing 55 per cent of chlorine instead of 64 per cent as in the case of the experiments reported in this paper and on a compound with a chlorine content between tri and tetrachlomaphthalene. We are also determining the degree to which the diet may increase or decrease toxicity, this being suggested by similar work The same gum acacia suspensions upon carbon tetrachloride. were injected subcutaneously into rats In the basis of these experiments :t ` . Mir It, no. 1\ ' "if04 * 4 i \ a n d on mai ;v d i f f e r e n t coc i t00TM3* ** ai | easil} that the air more than 0 ' /V.`of these co :- naphthalene. : compound cc are permias : many examh ^ v^ .pfanta that t ;-S^r.been greatly 20 years, anc 5 ^ ; . fact that o been *inexon 5";, human expos i-T*? ~ Time and c change these i \ \ but today we raafe. Impreg | - arrangements p* hydrocarbons taieguard. C lead.tetraethy CocBTOie-Suryr professions Ulne. Ana ' (1934). Ab . r : A,# jura M- professionnel V* ses drivs. 336 (1934). T u xn t F. B., aiti eertain chiori liver. Proc. SS, 118 (1936) Lwmawti, K. B .<Arbeite- und 1 Leipsig, 1 mU. U, ao. 1\ EFFECTS OF CHLORINATED HYDROCARBONS 299 and on many field determinations of different compounds in the air of work* rooms, it appears safe and it is cer tainly easily attained, to ventilate so that the air breathed does not contain more than 0.5 mgm. per cu. m. of any of these compounds above trichloraaphthalene. - 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 m ay 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 w ith benzene, lead tetraethyl and many other com pounds, these substances are very little toxic and operations employing them can easily be safeguarded. It m ay be argued that where possible trichlomaphthalene should be used, but this compound will cause acne and if employed very carelessly m ight do more. . Furthermore, higher chlorinar tion is often essential for highly prac tical reasons. The solution consists in thoroughly adequate ventfiation 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 w ith car bon tetrachloride'and depend on other solvents, especially upon those con taining no chlorine. BIBLIOGRAPHY Cocnrots-Scrm : tude tur l'intoxication professionnelle par le tricbloronaphUlne. Ann. de n (d . lgale, H , 432 (1934). Abstr. of paper by T oobainb, A., 4MB Mnthsl, B.: Dermatoses professionnelles par la naphtaline e t . ses drivs. Prat. md. fran., i t , SU (1934). Pwx, F. B., and Jabtix, N. E .: Action of certain chlorinated naphthalenes on the liver. Proc. Soe. Exper. Biol. A Med., U , US (1936). Is***! K. B.: Kursea Lehrbuch der Arbeits-uod Geverbehygiene. S .H ir" . Leiprig. 1919 <p. 251. ."* *k-- *. ..i M im u T lD T , O.: Gewerbeechidigunfen durch Haftax (Trichlornaphtbalin). Inaug. dissert., Jena, 1935. Tebbens, B. D.: Portable combustion ap paratus for field dterminations of chlorinated bydrocarbons. Tsxs J.t 19,204(1937). Telskt, L.: Die Peroakrankheit (Chloracne). Klin. Wehnschr., 8, 897 (1927). TounanrSp A., Solzntb, Mn<tes&, B., and Aubbun: Cinquante-quatre cae de ! dermatites par triehloronaphtaline. Bull. 8oe. dermat et eyph., 4/, 285 (1934). i . -> 300 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [SejX. js *7 D iscussion D*. Cecil K. Db in u b : We have had incline them to. First of all I shall ask quite a long morning, but since Dr. von Oet- Dr. Sayers if he will open the discussion tingen has to leave, I am going to ask him for us. to say a word. Da. R. R. Satxbs (Chief, Division of Db. W. F. von Oettinoxn (Director, Industrial Hygiene, National Institute of Haskell Laboratory of Industrial Toxicol* Health, U. 8. Public Health Service, Wash gy, Wilmington, Delaware) : I wish to con ington, D. C.): Dr. Drinker, Ladies and gratulate Dr. Drinker and his group on the Gentlemen: It gave me a great deal of pleas very interesting and excellent work on the ure to have the opportunity to listen to the subject. I also wish to congratulate the excellent and interesting discussion and Halowax Corporation on the fact that they presentations made this morning. Dr. didn't spare any effort to elucidate the prob Drinker, and I might add, the members of lem so that the dangers which apparently the Halowax Corporation, have discussed are connected with the use of this material this matter with us, as well as the manu can be controlled. facturers of the diphenyls. I personally believe that there is no toxic We have been doing some work but not material which cannot be used safely if it is nearly as extensive as that carried on here. handled properly. In order to handle such The work that we have been doing seems to materials properly during the different oper confirm the work that Dr. Drinker has car ations it is absolutely essential to be famil ried on. I think there are certain parts of it iar with the toxicity and especially with the that we can very well keep in mind. mechanism of the action. Since there is no We are dealing with toxic substances, but animal which corresponds in all its physio we are dealing with toxic substances each logical characteristics to the human being and every day in industry--harmful sub it is important that such compounds be stances, hazardous substances. That these studied with different species of animals so ean be controlled is well known, no matter that one can get a cross-section of the poten what they are, and that we can use them and tial dangers. use them in a safe manner. Dr. Drinker In addition, this fact illustrates the im has called your attention to the fact that portance of the pre-employment and peri this apparently has been done and ean be odical examination of workers in such work. done in any of the plants where halowax is As was pointed out by Dr. Drinker, there used. I have information from one or two are individuals who are apparently more of the other men who are in the audience susceptible to certain toxic agents than that in plants where damage has been done others. On the other hand, we have to try --kin damage and apparently liver damage to detect the very first signs of incipient to some of the worker--the manufacturers poisoning in order to prevent more serious have since corrected the conditions and ap damage. In the present instance it is very parently have adequate engineering con difficult to find these very first symptoms trol supplemented with adequate medical because there are no adequate methods, but control. I trust that in time the scientific profession After all, the proof of the pudding is in will supply the medical profession with the eating. If the man does not get the dis adequate methods which will allow the ease your engineering control is successful. physician to determine incipient damage of If he does get the disease, no matter what the organ before serious clinical symptoms you have done in the way of engineering, become manifest. you haven't been succeasfuL We must go Thank you. hand in hand. Neither profession alone A/Umoon Sutton ean be successful. We have got to work together whether we like it or not. I hap Db. Cbcxl K. Dbxmkxb: In this discus pen to like it. sion I will call on one or two individuals and There is one other thing. As far as mate I shall expect others to speak as their notes rials are concerned I think we ought to be rol. 19, no. 7] smart enough cessfully. If * adapted for a < it. Another z f V vioua to this f< was flammablt . approximately ~ say approximi sever just sur : It might have! :I. were quite tur . happened whe - with this mat< S fL ; electric cable. armor on the c - and was being ^ prximately 5 - t o a steel rop< j bottom of the e inspecting it 1 bide cap-lamp the fire killed mine. Many Here we ha __Now we have due to the U evaluate them I am informe< not just sure flammability chlorination k also increase! creases, accor think that che have these ha control them, wvcan. . Perhaps we are better eve present time ; - better. Iam submarines, it aon-flammabl , of their electri Dm. CbcxlI *; you can to sa & :: Dm. Albs M y of Occupation meeticut Dope / Conn.): Dr. E ^ anything that this material-j tof. 1$, no. 7) EFFECTS OF CHLORINATED HYDROCARBONS 301 J Vr . smart enough to use every one of them sue v cessfully. If this material it particularly adapted for a certain purpoee we should use fV it. Another material that was used prey vious to this for insulation purposes, which _was flammable, caused a disaster in which approximately 167 men lost their lives. 1 say approximately 167 because they were .HJ: never just sure whether it was 167 or 168. ? It might have been one or two more but they i- were quite sure that 167 lost their lives. It .fcF'y happened when they had insulated a cable with this material. They had an armored electric cable. I t was covered with lead 1 * armor on the outside. It was 1200 feet long j 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 Are with his car bide cap-lamp. The carbon monoxide from the fire killed those men th at 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, -- 1 am informed, are also flammable. I am i 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%th at we can. ^ - . Perhaps we can find other substances th at -sr.s.'.y 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 -V' ; eon-flammable substance for the insulation of their electrical wire. Da. CbcelK. D nontsa: Dr. Gray, would > *** C4rt * soy * word? ; Du. Au ix t 8. Omar (Director, Bureau : P ^ ^ y e f Occupational Diseases, 8tate of Coo- uecticut Department of Health, Hartford, Doan.): Dr. Drinker, I don't think there is ^ anything that I can say except that we used y y 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 touchwith 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. Da. Cscxl K. D a o r u a : May we now make the discussion general and those who have questions please volunteer. Mb. Manfred Bowditcs (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 eoatrol rather than by prohibition, which seems to ms wholly unnecessary not only in this case but in tho case of other toxic substances with which ws have to deal. The problem of proper ventilation seems to ms 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 th at 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 ego we issued a quite strongly worded warning letter to all plants using these substances and it has all along 302 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. 937 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 advocate 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. Sandford Bbown (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, 6 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. T hat is the problem we have had in this case. I t 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 trichlornaphthalenee. 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 i t 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. There may be some tetrachlornaphthalene, trichlomaphthalene, paraffin, a little pitch or bitumen, and possibly some chlorinated diphenyl. I t 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 th at 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 I. 19, no. 71 mr7-:? ' with which all are confronted synthetic orga meat is so rspi can't even keej ments sometux doing. -- Mb. F. R. agar, York Wii , York, Pa.): I th opportun \ reference to t our York plac -'again 1this < * ^ ` 5 the best teac % problem at \ through the < ..... it jjoniy 1 : neighborhood various degre 4 ..all know. E ' severely affiic \ . u their akin . r man died and - nted his de - vapors but a wj an strop of the autop* that it was work. Kno was employe lion that he thin, pallid not say fro physical ma be presents* ever, it was the time of plained o ft advised tha rapidly dev in the hosp died. More te r j that we hac " : don as far t o t react!* kad was tc plant: Th M i^V to tfo rtri said but n< Mid 9d . 19, no. 7] EFFECTS OF CHLORINATED HYDROCARBONS 303 frith which all manufacturer of chemical are confronted today, particularly in the synthetic organic field where the develop* ment is o rapid that our ales department can't even keep up with the research depart ments sometime, in knowing what they are doing. Mil F. R. Kaimsb (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 th at again in this case experience alone has been the beet teacher. I have lived with the problem at York with the men who went through the experience from its beginning. It is only 1} year 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. I t 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 I t 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, "W ell 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 quarts light, x-ray, mechanical removal of comedones and the treatm ent 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 elothing from street elothing to work clothing when they corns to work and the reverse of th at process, with the assurance that a shower will be taken before the street clothing is again put on, we have found ho 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 j %t when this thing starts. I believe it would be of great help 304 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sept. 1937 to us til in industry if some very fundament&l work w it done on humans, is Dr. Jones mentioned before we ctme into this meeting, some control in fundimen til work to determine some method whereby we m iy determine the inception of m y liver dis order. We have had our men examined in groups three times since the trouble developed and nothing his shown up in m y one m m . We hive learned and appreciate the fact that we must handle hasardous materials, but we have learned how to hmdle them. I t has been 1 very great experience for us m d for myself, and again the best teacher. Dm. Cecil K. D rinkxb: C m you recol lect the air concentration that you are main taining now with your present ventilating equipment? Mm. F. R. Kaimke: We have had two examinations made of the air by Mr. Wil liam F. Hemperly m d they average from 0.2 to 0.6 mgm. per cu. m. We recently dis covered one condition which was found aa 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. I t is in the form of a paste, reduced with solvent to a paste form, m d it was not known th at it contained a chlorin ated solvent in certain percentage. We dis covered it only recently through the analy sis of a sample m d we found that that was the cause of throwing the reeults off to a high value. I t was then about 8 mgm. per eu. m., I believe. T hat is going to be eliminated now. That is a combination of toluene m d carbon tetrachloride solvent. When that compound is exposed to the air the chlorin ated solvent odor is completely masked by the toluene. I t 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 m d we had no knowledge of the other being in there. Mm. Annum G. Bxrxn (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? Mm. F. R. Kamxm: They all returned to normal skin health, as I say, m d are work ing on the same job. Dm. Cecil K. Dmixcmm: Dr. Schwarts, you have seen a good deal of this general subject. Dm. Louie ScmwamTS (Medical Director, Dermatoses Investigations, United States Public Health Service, New York, N .Y .): I am primarily interested in dermatitis m d 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 cm only talk from personal experience about the skin cases. I know from what I have seen m d from what I have heard from doctors who have been treating these eases that if they are treated like m ordinary acne vulgaris m d 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 m d those who have superficial pustules or only come dones won't have m y scars. As far as prevention goes, I felt even be fore this investigation was undertaken that this substance, like m y other poisonous substance, cm be hmdled m d used in in dustry provided proper safety precautions are taken, m d I so advocated at the meeting in Pennsylvania when this was discussed. About ventilation m d safety precau tions, I think that while we eannot, with our present knowledge, detect by m y chemical tests the early symptoms of intoxication from this substance, the skin offers m easy way of proving whether your method of ventilation is efficient or not. If there are m y 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 ! ^ v V - e- coi* 11 ufficii S**t*S,e*-?i.c ; poisoo . sensiti bons. . *41 them, people stance diseas very d JRTt. in Ger Wh metho ` of ven if you any at this ns sufficic acne a be dai hypers ; I - - Dm. tical p i r mining pointe severs It has men w pie of learn ii confine ratus, compa toplac v tr '; I do the su an idei v- Mil - *-s; Hygiei u id , HetlU . >* -. minati would: _ . J*rly< x./'-jjtr'' * throuf tion 0: -- 7 Dm. as tha to di* : :y yr* V' Brand deters \ - ' a whil ralle M l. 9, 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 1014 or 1015. 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. D s. 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 confine our analyses to one piece of appa ratus, so that at least our results will be as comparable as we can make them from place to place. I don't know much about this phase of the subject: perhaps, Mr. Cook, you have ' an idea or two about that. Mb. 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 naphthalene!. D*. Cbczl K. Dbdtkbb: 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 a t least is, I think, a matter of gen eral interest to us. Mb. Warren A. Cook: I am not quits sure that I have in mind exactly what you want in that regard. In connection with sampling? Db. Ckcil K. Drinks*: Yes, In con nection with the whole technic of determin ing the material in air, length of sampling, type of apparatus, and so forth. I t 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 a t least have them on a comparable basis. Mb. Warren A. Cook: In th at 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. I t seems to me that one of the things th at should be done, which many of the plants and many of the organisations 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 th at 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 lending 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. i9S7 a t work with these material! but also hia before the A. P. H. A. in October as one of much smaller exposure and possibly even the projects which we shall carry out a t lack of exposure as he may go to other parte that time. of the room or even to other departments As I have not given this consideration, I during the course of the day. am afraid my discussion is not as connected Another type of determination which as I might wish it to be. We have a real seems to be extremely desirable to have is problem here and one that deserves some concentrations of the chlorinated naph study. thalenes at certain reference points. I believe that Mr. Hemperly very carefully Da. Cecil K. Dbinxxe: Would it be of duplicated these reference points in each service to the American Public Health Asso of the plants where he took his determina ciation Committee if a sub-committee from tions. He took the samples, I believe, a t this meeting, collected perhaps by my breathing level and a certain measured dis brother and those of you involved with these tance from the pots where the chlorinated problems, were to make a recommendation naphthalenes were being handled, so that to the A. P. H. A. as to the things you have next year he could go back to those same brought up and as to suitable apparatus, locations or others could take determina and let the final statement come from the tions a t those same locations, which are Association after they have considered th at definitely fixed and recorded, and learn material? whether, due perhaps to clogged pipe lines or to fans which might become loaded with Mb. Wajuuen A. Cook: I think th a t the condensed chlorinated naphthalene, would be a splendid idea because we have there might be poorer ventilation than origi a bulk of information on this particular nally designed and higher concentrations material. number of individuals have of the chlorinated naphthalene than origi given much thought to the development of nally determined. apparatus, both the combustion method It seems to me that it would be an ex which we have here and also the continuous tremely desirable thing to have made avail record type of apparatus which Professor able for all of us who are making these Drinker mentioned this morning. I think determinations these reference points so that it is a sufficiently important project that in Massachusetts and in Connecticut, that a sub-committee made up from this a t one plant or at another, a considerable group could give th at committee a very group of workers could be taking samples at definite steer. this one particular point with reference to [Personnel of the Sub-committee: W. A. the source of generation of the vapor. Such Cook, chairman, A. L, Coleman, H. B. El results would permit a comparison of know!-' kins, W. B. Fulton, S. W. Gurney, E. R. edge between plants. Hayhurst, Wi F. Hemperly, F. W. Sehl, and In that regard it happens that there is a A. N. Setterlind.] committee of the American Publie Health Association which is charged with the devel Mb. Hsbtbt B. Elkins (Chemist, Divi opment of chemical methods for determina sion of Occupational Hygiene, Massachu tion of atmospheric contamination such as setts State Department of Labor and Indus that now under consideration. I t seems to tries, Boston, Mass.): In connection with me th at it might be a very desirable project what Dr. 8chwarts has said, I am not sure for th at committee to consult with the in th at I am in complete agreement as regards vestigator of the Halowax Corporation and the use of skin lesions as warning agents. suggest to all of those who are doing work I t is my understanding that in insulated of this type, after some discussion, what wire plants the chlorinated diphenyls are reference points could be adopted and also very commonly compounded with the chlo what should be done in connection with get rinated naphthalenes. I t is also my under ting these average exposures. Asa m atter standing that these are more likely to cause of fact our committee will discuss th at very a severe akin irritation than the straight feature and possibly include it in our report chlorinated naphthalenes. On the other <r m*. 19, no. 7] EFI hand, from Dr. Drin \W k judge that the straif tbalene was nearly a mixture of it with a ; !; ILv '-vL, rinated diphenyl. In the condenser 1 our cases there is no used and no acne of the reports on the mi 1^ ~7 [ 'D a. R. Emmbtt Ki leal Co., St. Louis, M anything to the labor: has been quite a littl tion in the last sever our plants where we 1 ing this chlorinated < our observation that sion we did have a i series of skin eruptioi able to attribute as t< impurity in the bens< the chlorinated diphe any systemic reactic We have examined t from what laboratc might help us and f point. Also from alone there have bee poisoning reported. I don't believe ths laboratory results ir without paying eon the volatility of die< way they are being Da. John A. Hoc \SjfSj- matologist, Halowax Mich.): I have had < i i i r - . .with the dermatolog lem. The experienc st Wyandotte definit tosis did increase * used rather than tl naphthalenes. From the discusai I think the observe' that the chances bj problems will disapp l is probably true. 1 i>. certain precautions, ..ures, you might as - hiring men who~ar `th* ~*oducts, eve 3 9ol. S9, no. 71 EFFECTS OF CHLORINATED HYDROCARBONS 307 hind, from Dr. Drinker's work one would judge theft the straight chlorinated naph thalene was nearly as toxic aft least as the mixture of it with a small amount of chlor . 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. D*. R. Emmett Kelly (Monsanto Chem ical Co.f 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 manufacture __' ing this chlorinated diphenyl. It has been our observation that although on one occa sion m*e 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 bensene 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. -'-VTr: He. John A. Hooxet (Consulting Derlr/; maftologist, Halowax Corporation, Detroit, .c . Mich.): I have had considerable experience with the dermatological angle of this probv >; lea. The experience at the Halowax plant . v at Wyandotte definitely was that the dermak**9 did increase when compounds were rrlrl^ .u e d rather than the straight chlorinated .naphthalenes. From the discussion we have heard today i y^nk the observation Dr. Drinker made , ^ chances are that dermatological ; .problems will disappear along with the other ^ true. However, I think th at - >certain precautions, certain insurance meas- 7o might say, should be taken in v-^Sfr^L^ring mei| who are going to work with Products, even though we are going to attem pt to get the concentrations low. We saw this morning that the effect of these products w u 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 testa 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. Mb. F. R. Kum ee: I would like to clarify a point of Dr. Hookey*. You mentioned a t 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 lees harmful in so far as acne is ooncemed or is it because of the handling of batch compounds! Dm. J ohn A. H ookby: 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 eases after I started working with them the men in the plant said 308 JOURNAL OF INDUSTRIAL HYGIENE ANJ) TOXICOLOGY [Sept, m r 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. Mb. F. R. Kaimer: You say that the con dition increases with the increased chlorine content and we are attributing the acne pri marily to the chlorine radical. If that is true, what are we to associate insofar as these various other constituents are con cerned, such as various plasticising agents? How much do we know about those insofar as development of acne is concerned? 8ome of these compounds have a half dosen con stituents in them other than chlorodiphenyi and chloronaphthalene. We are a t 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. Hookxt: I don't know about these other materials. Perhaps Dr. Schwarts would know something more about them. Dr. Louis Schwarts: 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 Company where they make chlorinated di phenyls and they have aene there just the same as over a t 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 eomedone 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, 80, 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 1 recently read an article in a German magasine in which they report in Germany a similar acne condition from chlorinated phenols and chlorinated benzenes and solid waxes. It seems that this acne-like condi tion is not peculiar to halowax or chlorin ated naphthalenes or diphenyls but can occur with any condition that blocks up the sebaceous follicles of the skin. Dr. Rotal Mxrkxr (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 ss 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 poree of the skin and the poree 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 a t all. There is no question there 90l. I -Sz St: "vuv; - t ben* . % - ` W. sene \ venti & s r ; . ,ume '>P v insU ,ol. /p, no. 7) EFFECT8 OF CHLORINATED HYDROCARBONS 309 that the condition, whatever the complice* tione might have been, c&me 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 Rockbestos Products Corporation to tell how they have handled it. If I am any judge of equipment and -- --- safety devices they have come as near *to eliminating entirely from the atmosphere all 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 bensene 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 th at 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 th at 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. Da. Royal M m : What is the veloc ity when the door is open? * M i. B. H. Ru y s s (Vice-president and General Manager, Rockbestos Products L Corporation, New Haven, Conn.): I will be very glad to tell of our experience if it will .. . help the picture along. Our experience has ~ been more or less parallel with Mr. Kaimer's T .. _ *s much as we manufacture the same type of wire. We have avoided the serious picturn that he ran into, probably due to the . . * feet that shortly after 1023 we were using .~ r bensene as a solvent for asphaltic materials. - * We got into anemia difficulties with ben**&e fumes and had to install a complete ntfiating system to remove aU those js V ; . fumes from the machines that applied the ' v oomPunds to the wire. Following the . tatallatioa of that equipment we were able " -T^T*; * * substitute for bensene, so we got it - -rV?-.:?. otl** the picture. - We are still in the same fix as every one Is as far as finding a substitute for haloWIL There is none that we know of. Con- Kocotly when we went to the use of halo- Ma. B. H. R u m s : With the door wide open, at breathing level the velocity is 200 feet. That is the linear velocity. We check that every week on every opening at every machine with a velometer, a small instrument which is easy enough to operate and reads directly. Whenever the velocity falls below that figure the pipe connecting that machine is taken down and cleaned, because there will be condensation inside the pipe to cut down the air flow and reduce the ventilation efficiency. Dn. Royal Mi x u i : What do you think of that trap device shown? Ma. B. H. R u m s : I don't know what to think of that. I don't know whether it would be practical or not. I was going to ask Dr. Drinker whether in passing the air laden with halowax fumes through the boxes of rats there was any deposit of halowax in . the enclosure. 310 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sepf. t9S7 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 post 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 a t all in the case of liver damsge in this msterialf Dr. Exert. R. Hathurst (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. VoaitJROH (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 ail sorts of things. I am not a t 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 oomplaining. We thought we were having a hysteria of halowaz 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. Vosburoh: 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 ease we set aside a certain number of animals to recover, after knowing that a certain amount of damage had been dons. 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, Vosrurgr: Have you given them calcium and glucose as you would with carboa 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. ! ^ if, no. 1 EF Dr. B. L. Vosat questions in mind, what Mr. Brown wo `` - bility of using on! W r ; .chlorinated naphthi * Mr. Bandford f simplify our proble; ! * . from the commerci -y'V- .the toxicity standp y\# 5 ' I think that Mr. K to object because h " the technical effect : The same thing ap industry where w< .chlorinated produc * The problem as fr . which we intend b 5 %*- our program for tl will be done une -- . . Drinker brother) - demarcation and i - - S i - complicated cher ? eoros one thing th ' could take h remove I percent J ueot with which and eliminate th - .... a lovely solution. able to attain th one of the things As I said befoi with which all nc thetic organic p some stage, eithc commercial dev question of timii tbs work, how whether you kn< to learn that fin V;v Dr.C*clK ` some other imp the meeting ad \;x/ \ D. R. R. ; more with rega. . on syphilis? 1 /; v f ; all tout work c. .. ; of. /$, no. 7] EFFECTS OF CHLORINATED HYDROCARBONS 311 Db. B. L. Vosburos: I just h id those questions in mind. 1 would like to hear what Mr. Brown would say as to the possi bility of using only this one innocuous chlorinated naphthalene. Mb. Sandford Brown: T hat 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. aim er would be the first ' ` " to object because he wouldn't be able to get the technical effects he desires in the cable. The same thing applies throughout all the industry where we are using these higher chlorinated products. The problem as we see it, and it is one which we intend to study further (we have our program for this continuous work that will be done under the direction of the Drinker brothers), is to try to find a line of demarcation and whether or not within this complicated chemical structure there is some one thing that causes the trouble. If 1 we could take bexachlornaphthalene and remove 1per cent of some unknown constit. uent with which we are not now familiar f and eliminate the toxicity, that would be I a lovely solution. Whether we will ever be able to attain that I don't know. T hat is one of the things we have in mind. As I said before, that is one of the things with which all manufacturers of these syn- thetic organic products are confronted at some stage, either in their laboratories or in commercial developments. It is largely a question of timing as to when you should do v the work, how much you should do, and \ whether you know how to do it. You have to learn that first. . .; t y/i-fv Db. Cecil K. Dbxkeeb: Unless there is : omt other important m atter I will declare .Iw the meeting adjourned. . Dm. R. R, 8atebs: limy I say a word nre with regard to what Dr. Hookey stated - g i t bn syphilis? If you are going to eliminate 'all jo u r 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. Mb. 8ANnroBD Brown: I want to take this occasion to express on behalf of the Halowax Corporation my thanks for the excellent cooperation we have received from various state authorities and our customers as well in this investigation. I believe you have all formed the opinion, based on what you have heard this morning, that our whole motive here is to conduct this on an ethical, scientific and constructive basis. In collaboration with the Monsanto Chemical Company we have a much more comprehensive program in view to carry on. Therefore we want to continue that same type of cooperation. There is one thing that I want to bring up in that connection, which will have to be observed by the state authorities, when they go out to make these inspections. That is the necessity of not creating mob hysteria on the part of the workmen in the plants where these inspections are made. Mr. Hemperly has run into some very interest ing situations in the various examinations he has made. I know that he would be glad to relate them and give the benefit of his experience to the heads of any of these state departments who will have the direction of this work. Otherwise I can see where we will be unable to get the full cooperation of not only the individual workmen but the plant foremen and the management, and we must have that if we are to get the results that we are shooting for over the next sev eral months or years. This thing may con tinue, probably will continue for years. .