Document r6Qd9YKmQp9ogGG2zy9kmOj8a

THE PROBLEM OF POSSIBLE SYSTEMIC EFFECTS FROM CERTAIN CHLORINATED HYDROCARBONS* Cecil K. Dkineeb, Madeleine Field Wamibn and Ghanville A. Bennett Department of Physiology, Harvard School of Public Health and Department of Pathology, Harvard Medical School, Boston, Mast. HE use of chlorinated naphtha rapidly and thoroughly as possible, t Tlenes and compounds of allied pharmacological possibilities is In brief these cases were as follows: Patient 1. Male, age 21. The preview extremely wide, and with the steamdeydical history of this matt was in no way growth of the use of electricity is cer significant except for the fact that be had tain to expand much farther. For jfeftrs it has been known that many of theso compounds cause a troublesome acne, and there is a large literature an attack of jaundice about 0 weeks prior to his fatal illness. Late in December, 1930, be became badly constipated and had murh abdominal pain and distention. When ad mitted to the hospital he was slightly jaun upon this phase of the subject. Our diced and was evidently very ill. He was investigations have not been concerned with ehloracne but with the possibility of systemic effects following ingestion or inhalation of such products. In the somewhat anemic and his skin, particularly upon the arms, face, chest and back, showed many pustules. He died after a brief period in the hospital, and at autopsy was found to spring of 1930, the Halow&x Corjtoratk>n, a division of the Bakclitc Cor poration, called our attention to three fatal eases of jaundice in workmen using chlorinated naphthalenes and chlorinated diphenyl, and requested that the subject be investigated as * Received for publication June SO, 1087. | The Ilalowax Company makes many products besides chlorinated naphthalenes, and it has come to our know ledge that all of these products are indiscriminately called "halowaxce" by purchasers and usera, and are lumped together as possible causers of aene ana even of systemic disease. Since "halowax" is merely a trade designation, rare should be taken to describe compounds by tbeir chemical name* and thus avoid condemnations which are both troublesome and misleading. MQNS 097358 284 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [8*pt. 1937 have cirrhosis of the liver with acute yel low atrophy euperimpoaad upon it. This man had been exposed to low concentrations of vapors arising from a mixture of tetra and penterhlornnphthalenes, together with approximately 10 per cent of a refined chlo rinated dipheuyl. While both he and otbora engaged in the same work had chloracne, there were no other disturbances of health in fellow workmen, nor wan there any pre cipitating cause for the acute yellow atro phy such as treatment with arsphenamine or exposure to dangerous concentrations of carhnn tetrachloride. Patient I. This waa a young man who died in February, 1936, after an acute illness ehnraeteritcd hv jaundice. He had been exposed to fumes arising from a mixture of penta. and hcxaelilornaphlhalenes. There is no record of chtorarno. The patient worked with a large number of other people of whom hut one (Patient 3), a closo friend, had significant illness. Patient S. Another young man employed with Patient 2. He became jaundiced in March, 1936. and died after an illness of 2 weeks. A careful autopsy resulted in a diagnosis of acute yellow atrophy of the liver Here again no history could be ob tained as to a precipitating cause, and thero waa no record of preceding attacks of jaundice. In Addition to these three very re cent fatalities, wc have learned of four other possible cases, none of them fatal. All of these have had jaundice and the entire group consists of iso lated individuals who have been picked out of large groups having the same exposure. In but ono instance, Pa tient 1, is there record of antecedent disturbance of health, and the general health of fellow workers has been good. Such cases have not been reported in the medical literature and only occa sionally can one find reference to sys temic effects of any sort. For exam ple, Courtois-Suffit (1934) reports on work done by Touraine and his asso ciates (1934) who examined 00 workers who had been cxj>osed to trichlornaphlhalcnc. Of these 13 were found to have mild digestive complaints, anorexia, nausea and vertigo, but Courtois-Suffit remarks finally, "Ab sorption is certainly possible and we have for proof of it sonic of the diges tive and general complaints which have been due to it. But they appear to be of little consequence considering the mildness of the digestive troubles and the absence of respiratory phe nomena." In Touraine's cases t he exposure was to a trichlornaphthnlcnc, whereas the American cases of acute yellow at rophy were exj>osed to compounds of higher chlorination. Our own experiments indicate that trichlornaphtlialcncs re quire enormous dosage, far beyond anything encountered in industry, in order to produce liver damage. Tclcky (1927) rqwrtcd a number of coses of chloracnc in persons cxjwsed to chlorinated napbthnlrnes with a chlo rine content ranging from 14 to 53 per cent. He found that the lower the chlorine content the less the acne. Mittclstadt (1935) examined a number of cases of chloracnc due to trichlornaphthalcne and retried a number of vague general complaints but nothing in the nature of serious disease. Re garding bis animal experimentation, Lehmann (1919) reported that ani mals fed chlorinated naphthalenes re fused to cat after a lime and that, whether poisoned by inhalation or by feeding, at death showed "peculiar" lesions in the liver. Flinn and Jarvik (1936) gave subcutaneous injections of enormous doses of chlorinated naph thalenes dissolved in paraffin oil to rabbits. The compounds used were as follows: MOMS 097359 |5pf. tur . trichlorwere found inplnintft, :i*n, bul lly, "Ab- And we the diges ts which ry Appear unindenriR c troubles lory phe- ifure was acres* tho .v ntrophy of higher periments ilenes rer beyond tuftlry, in ge. Tolr of earns uxwed to . h a ehloio 53 per iwer tho he aene. . number 1 uiehlor-umber of ; nothing :*c. Re.filiation, iliat anilionet re nd Dial, hi or by peculiar" <i Jarvik rtion* of d iiaph oil to 'd were Ivl. 19, no. 7| EFFECTS OF CHLORINATED HYDROCARBONS 285 1. A mixture of tri nod tetracblornaphthalcnc. 2. A mixture of let mi and |>cntRchlornaphthalctic. 3. A mixture of |>enta And hexachion>aphthnlriic. In addition, sublimates from (2) and (3) were collected in oil and injected subcutaneously. None of the animals receiving (1) or the sublimate from (2) died, and even after 2 months were (piite normal when nutopsied. The first death in the ani mals receiving (3) occurred on the 12th day and the last died on the 2Gth day. Those receiving the sublimate from (3) were even more severely affectid. Autopsy in these animals revealed striking changes in the liver, not, as described, entirely characteristic of acute yellow atrophy but sufficiently suggestive to rausc the authors to con clude that "certain chlorinated naph thalenes or impurities contained in them are capable ol producing yellow atrophy of the liver in the rabbit." At the beginning of their pn|>er, Flinu- and Jarvik (1930) mention the fact that there lmvc liecii three cases of acute yellow atrophy of the liter in mcti working with chlorinated naph thalenes Imt give no details in regard to them. These cases arc undoubtedly the some as those described in the beginning of this paper. Cue may summarize the meagre literature uj>on systemic effects from these substances as follows: 1. With the exception of the men'tion of aeutc yellow atrophy by Flitm and Jarvik (1930) there are no report* 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 (1930) 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 arc 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 Flitm and Jarvik (1930) point to tiie liver as a |xssil>le site of injury (his indication rests upon such extreme dosage as to fail to apply directly to human cxjiosure. KxrrmtMKNTAL Wohk In appraising the possible toxicity of any substance met in industry it is first necessary to determine the prin cipal route of absorption. In the case of the coni|M>unds under consideration there can be no doubt that inhalation is their chief means of entering the body. They are used hot in a great variety of operations and volatilize in varied degree. They are often applied in solution in such volatile solvents as carbon tetrachloride and toluene. The amounts reaching the air under such circumstance* arc hardly detectable. It will however l>c shown that- carbon tetrachloride adds to the toxicity of the chlorinated naphthalenes and allied com|)Ounds, 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 a.- toluene should be used. Observation in a number of plants causes us to feel that even though MQNS 097360 2SG JOntXAL or IMH'STKIAL HYGIENE AM) TOXICOLOGY {.$*. tST workmen may be extremely dirty and cartlew, comparatively little of these waxes is eaten. They nre tenacious substances, insoluble in water, and if they Ret on the hands they stick there and are not transferred to the food. Skin absorption is the third possible menus of (-uterine the body. It- may occur but at best must be slight when compared to the steady inhalation of finely divided or gaseous material in t lie? air. tion. They thrive upon a diet very similar to man, and in the rase of these chlorinated eom|>onmis it is jwssible thnl diet may be very significant. Finally, their norma) characteristics have been described so well as to make the detection of abnormalities both easy and certain. Method of exposure.--The inhalation experiments were carried out in four large air-tight wooden lioxcs, curb capable of holding ten rat cages, sm* Fio. 1. Front view and inflow end of two boxes with rat rages in place and doors open. Inhalation experiments arc then the most im)>ortant sources of information, hut to them we have added a certain number of olavrvation* uj>on ingestion and subcutaneous injection of various compounds. Inhalation Experiment* AnimoJr--White rats have been employed throughout. They permit the use of a large number of animals in a relatively small inhalation installa- 22' x 22' x 14', in two tiers of five rages each. When the experiment was not in progress the doors were opened wide and the cages kept in place (figure 1). At the center of one end of each box --the inflow end -air was introduced ..through a pipe 7 inches in diameter (figure 2). Each box was equipped with An individual variable-speed elec tric blower which blew the air through several feet of 7-inch pipe l>cfore onter- tol, IB, inff tl meter t he fit could from deflect' pipr it sure i st rean At t otilllni was e* fitted a Inrgi Aim the 7-i of the dotted c tally (figure diamet hold tl were I hat e top of this fit leneth. into a I tightly pi|M> on fln>k in heater )k*1ow t top. ) side an voir nre throng! motion Into cm ccntigr* kept in time al' which it A|i|>rr dilorinn pm ipi nyi qgi MGNS 097361 ,,i. 1991 i very i thn* ,,vdble llii'llllh .ristio* mnkr IkMIi lulntkm i* four each Kite * j i i f five t HU trued |*Ih! h Ihix i*4uwd meter iiMfvcd I "irIi titer rol. 19, no. 7! 1CFFECT8 OF ('m.01tIXATEJ> HYMKOCAltltOXS 287 ing (ho etui of the box. An orifice meter was placed in the pipe line, and the flow of air in cubic feet per minute could be adjusted and rend off directly from a calibration curve. A vane deflector placed at the entrance of the pipe into the Imx was adjusted to as sure n uniform distribution of the stream of air to the two tiers of cages. At the opposite end of the box--the outflow end--(he air from each Imix was exhausted through a 7-inch pipe fitted with a <lain|K r and connected to a large central exhaust fan (figure 3). Alxmt 4 inches from the entrance of the 7-inch pipe inU* the ls>x, the fumes of the substances listed wore intro duced into the inflowing air. Spe cially designed pyrex glass flasks (figure 4), 7J inches long and with a diameter of 1 i inches, were used to hold the heated waxes. These flasks wviv mmle with a side nrm and lulie that extended to the Injltom. The top of the flask was ground, and into this fitted a short tuU* 1$ inches in length. This short tulie was inserted into a large rubber stopper that fitted tightly into a hide cut out of the 7-inch pijx* on t he under side (figure 2). The flask in turn \vs placed in an electric heater made to cover it completely below the side arm and ground glass top. lluhbcr tubing connected the aide arm with a compressed air reser voir ami a gentle stream of air blown through the melted wax kept it in motion nod 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 pijx* through which it passed (figure 2). Approximately 30 gm. of pulverised chlorinated nuphthalenes or 20 gm. of chlorinated diphenyl were placed in the Ixdtoni of each flask and melted in the electric heater. Fresh samples were Used every other day, but it was often found necessary to add 20 gm. of new material even after one run since so much had sublimed. Whatever the ease, the collected sublimate was FlO. 2. Electric heater (nr inniiitiiiiiiny chlorinated compounds at a constant ternin'rulurr hi plncc at inflow end of box. always removed from the tipper 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 waa care fully weighed at (he beginning of the nin and at the end, and the low in weight used to calculate the average MONS 09736^ 288 JOURNAL OK INDUSTRIAL HYG1KNK AND TOXICOLOGY [Sept. 1937 nmount in a cubic meter of air per minute ns determined by a series of Kki. 4. I'yrcx jdsns flank 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 Ih)X, but they cheeked well with direct ^determinations through air sanipLc-Sr Approximately 1 hour was allowed for the wax in the flasks to melt, and come to a constant tcm|Hratutc. At that time the tax doors were tightly closed, air bubbled through the flasks, and the blowers turned on. This was the beginning of the e.\|>osure 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 nn attempt was made to keep the four taxes as uniform as possible- usually between 11)5 and 175 c.f.m. In the first group of experiments the following substances were tested: 1. A mixture of Uichlomnphlhalencsplusn trace of tetrachlornopthalene. Chlorine content 49.9 per rent. 2. A mixture of jwiita and hexachloruaphthalenes. Chlorine content 02.G jkt cent. 3. A mixture of 90 icr cent penta and hcxachlornaphl halcncs plus 10 |>cr cent refined chlorin ated diphenyl. Chlorine con tent 03.0 )>er cent. 4. Chlorinated diphenyl. Chlorine content 05.0 j>cr 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 mJ. It I)og <W. Tk bR expo chlnr lGtU COtltj 18th tivc sun* kilk 15th (ONI I Trie | tM | Pent I fiOTt i leti I ! Chi- per the gro cxr for T 1C Eft. ces 4:C wc for flu HONS 097363 f*r ! of iiR p of ln*r-of .Ml* air mil uiid At Inly WB* iod. ntid Um* the m|l < Hi wm the lIlBilorlent icxtrinr -nta ivopn Tin- iron- > Tine ro|K rinn'trial ntil'need irina sol. 19, no. 7J EFFECTS OF CHLORINATED HYDROCARBON8 289 Dor Chow supplemented by lettuce, eggs, milk and cod liver oil. This first group of experiments was begun on July 1, 1930 and the last exposure to number 2 (;>cnta and hexaclilornaplithalcnea) was on November 10th. The exposure to the otherthree eoinjKJundii ceased upon November 18th. On October 15th representa tive animals were taken out of expo sure from groups 1, 2, and 4 and were killed after 2 months on December 15th, in order to seo 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 evory night be tween 10:00 and 12:00 p.m. ns well as on starting and stopping. At dif ferent times during the course of the experiment tests for free chloride were made but were uniformly negative and TABLE I. Conditions Maintained in Inhalation Exterisient rnoti Jult 1 to Novkmkek 10 and 18 MITMHL ru>mvi TENT. CONTENT AT. CONCENTRATION or AIR IN kOX TOTAl. AT, RAlLT FOOURE XXroauRt % c. mf./nt. rmn$t imri ieur* Trichlornaphthalanc* plus traces of telr&ehlorrutphlhalene..................... 48.8 100-160 1 31 High 2 60 Low 0 10 1606 16 Ponte and hoxaohlornaphlhalcnea.... 92 fl 160-170 1.16 High 2.10 1801 Low 0.51 10 80% pent* .and hexachlornaphthalonea plus 10%chlorinated diphenyl. 63 0 165-176 1 37 High 3 17 Low 0.64 1806 16 Chlorinated diphenyl.......................... 65.0 185-175 0 57 High 119 1890 Low 0 23 10 period would bring about recovery in the affected livers. Animals from group 3 were similarly removed from exposure on October 4th and killed for examination on December 4th. The average length of exposure was 16 hours daily for 6 days a week. Each morning at about 9:00 exposure ceased, and between this time and 4:00 p.m. the rata were cleaned, fed, weighed, etc. In order to secure uni formity of exposure the cages were shifted on a regular schedule, since showed that under the temperatures used no decomposition occurred. Tabic 1 shows the temperatures at which the various substances were held, the average concentrations per cubic meter of air, and the average exposures from July 1 to November 16 and 18. The concentration of chlorinated naph thalene* and chlorinated diphenyl in the air of workrooms.--Table 1 shows that animals have been exposed to varied concentrations of the substances under MQNS 097364 UbMMm> 290 JOURNAL OP INDUSTRIAL HYGIENE AND TOXICOLOGY ISepf. 19ST teat. The conccntrnt ions employed may regarded as fairly representa tive of industrial experience. Prior to the initiation of inhalation experi ments a number of estimates of chlo rinated hydrocarbons in the air of dif ferent factories were made and the Suction 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 wit h sodium carbonate containing a trace of sodium sulfite. The beads are then washed down and the chloride deter Fio. 6. Dimensioned sketch of combustion tube and absorption apparatus. concentrations chosen for inhalation experiments depended on these exami nations. The technic of analysis and the apparatus employed were the work of Frederick E. MUlhiscr and William F. Hompcrly. The method and apparatus used for determining concentrations of chlorin ated hydrocarbons in air were adapted from well-known procedures. The air mined ncphclomctrically as silver chloride. Tebbcn.s (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 ua in both our laboratory and field problems. The absorption tube is l I vof. 19, no r somewhat c i j Tebbens's Imt devices an* th | In both cn-< rinated hydro acid ami m,'. sodium eailw t In our ett.-t* o * apt lo he vt-r i less titan 1 m qucntly the x actually fnrnw so small that v | cither gravim* For this re:t use the m-plifl | is sciudtivc t< as 0.1 mgiit. f It is doubt: should exeevd conversion cu pound to liv> sub&cqui'tit :d` unless the vili low. Ano11111 is that the m [ auy clilorin'j. determined, dutinguish hr gases but deter | the resuiti i puted in tew At the pw | formation m rinated nnpht | different phii* instances the repeated sev* the amount.* thoso used in must be n-m I i * Th* roinliit | ratus suited by Willson Yr* The cquipm.'it tuetioD pump' HONS 097365 90t. 19, no. f) EFFECTS OF CHLORINATED HYDROCARBONS 391 somewhat easier to wash down than U TebbensV but the essentials of the two devices arc the same.* In both eases conversion of the chlo rinated hydrocarbons to hydrochloric acid and subsequent absorption as odium carbonate should be complete. In our case concentrations in air are apt to be very low--the objective is less than l mgm. per cu. m. Conse quently the amount of silver chloride actually formed in the final reaction is so small that it can not be determined either gravimctrically or by titration. For tins reason we have been forced to use the nephelometric procedure which ia sensitive to concentrations as low a* 0.1 ingin. per cu. m. of air. It is doubtful if the sampling rate should exceed 1 liter per minute as onversion of the chlorinated com pound to hydrochloric acid and its subsequent absorption are not efficient unless Uic velocity of the gas stream is low. Anot her precaut ion to be noted is that the method is not selective-- any chlorinated substance will be determined. Furthermore it does not distinguish between solid particles and gases but determines them all alike and the results must, of course, bo com puted in terms of total chlorine. At the present time we possess in formation as to the amounts of chlo rinated naphthalenes in the air of 30 different plants, and in a number of instances the measurements have been repeated several times. Frequently the amounts have been greater than those used in our experiments, but it must be remembered that the rats Tbs combustion nd absorption appa ratus suited to field sampling is now made br Willson FroduoU, lne-, Reading, Fa. Tin equipment includes flowmeter and eueUoa pump with a carrying ease. have been exposed for 16 hours to an atmosphere constantly impregnated with the substance under test, whereas human exposure is usually a variable quantity, intense for a short time and then negligible. It is our opinion at the present time that the concentra tions of chlorinated hydrocarbons used in our experiments would be dangerous for workers in the case of compounds above tricblomaphthalenc in chlorina tion. Fortunately it is easy to venti late processes of manufacture which require these substances and to reduce air contamination practically to the vanishing point. Such treatment of the problem at once removes both the possibility of systemic poisoning and the annoyances that arise from cases of acne. RomiU* of Inhalation Experiments. 1. Animals exposed to a mixture of trichlornaphthalenes plus small amounts of tetrachlomapthalcnc. Living animats were apparently en tirely normal. Autoftsies performed near the end of exposure seemed to show slight swelling of the liver, and microscopic examination occasionally showed swollen and hypcrgranular liver oells, The changes were, however, never more than slight. 2. Animals exposed to a mixture of penta and hcxachlomaphthalcncB. No abnormalities were observed in the living animals. Hats were killed and autopsied every 6 weeks. In the first animals sacrificed liver changes were observed. These were swelling of cells, slight granulation and hyalinina tion. In September and October these conditions were somewhat more ad vanced, and in November the process became stationary. There were highly I MGNS 097366 ] 292 JOUHNAL OP INDUSTRIAL HYGIENE AND TOXICOLOGY [Stpt. 1937 90I. t9, t granular cells, hyaline inclusions and mitotic figures, but no more than 2 months previously. 3. Animals exposed to a mixture of 90 per cent penta and bcxacblornaphthalcncs plus 10 per cent refined chlorinated diphenyl. No abnormali ties were seen in the living animals. After 0 weeks the livers showed changes similar to those in the animals exposed to penta and hcxachlornaph(hfllrncs. These advanced in grade during August and September and then became stationary. 4. AnimaJf exposed to chlorinated diphenyl. No abnormalities were seen in the living rats. After G weeks' exjXMiire then? was slight liver damage which advanced during the next 2 months. The changes consisted in slight to moderate swelling of the liver cells, an increased granularity and many mitotic figures. Ilyalinixation was always present as a result of inhalation of chlorinated diphenyl. Summary of the first inhalation ex periment.--Iu these experiments care ful observation of appearance, body weight, activity, blood, and urine showed no abnormalities of any sort. Yet after G weeks' exposure all the compounds with chlorination above trichlornaphthalcne caused minor de grees of liver damage, and no changes whatsoever in other organs. There was no acute yellow atrophy or any thing suggesting it except that a slight degree of liver damage was always present and was quite clear in the liver sections examined microscopically. This damage had no detectable effect on the health of the animals. They held their weight, ate and behaved normally, being in every respect similar to the many people who have been exposed to these compounds without illness of any sort. The functional appraisal of the liver damage caused by certain chlorinated naphthalenes and by chlorinated di phenyl.--There arc no testa of liver function useful in 6uch 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 exrcption of the fact that in iso lated instances jaundice 1ms occurred which upon at least three occasions has gone on to acute yellow atrophy. During recent year9 this disease has been seen following administration of carbon tetrachloride, arsphcnainuic and cincophen. In the ease of carbon tctrachlorido 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 arspbenamme, but somehow or other this now and then does happen to pa tients under antisyphilitic treatment. It occurred to us that something of the same sort might be involved iu this problem. The human cases have been scattered and few. They have been isolated instances out of large groups of healthy employees who have had equal degrees of exposure. It was our idea that perhaps many of these people got liver changes such as existed in our rats, changes not recognizable through f i l I I I l \ any mr nation, such rl disturb not a which i this n over t< Knn had li slight ' we dot substn st rucii ftltohc mat im clilorii per ki nonm to 0.1 0.75 f Tin tube Tiiuls ; follow Rats ) 1. 7 cMon 10. 10 2. / at 9:3 3 1 1 1 S. (hale Fed MQNS 097367 Y vol. 19, no. 71 EFFECTS OF CHLORINATED HYDROCARBONS 203 an}' means other than autopsy exami nation. If, upon the substratum of such changes, they got an acute liver disturbance, acute catarrhal jaundice, not a very common disease but one which any of us may experience, would this relatively innocuous disease go over to acute yellow at rophy? Knowing that our inhalation rats had liver changes, but changes too alight to cauae recognisable symptoms, we decided to teat their resistance to substances known to cause liver de struction, Carbon tetrachloride and alcohol were selected. Having infor mation that 1.0 cc. of carbon tetra chloride plus 1.0 cc. of ethyl alcohol per kilogram would kill 14 per cent of normal while rats, we reduced the dose to 0.75 cc. carbon tetrachloride and 0.75 cc. of ethyl alcohol. This mixture was given by stomach tube to the following groupa of ani mals and with the results found in the following tabulation. flail fed 0.76 cc. per kgm. each of carbon tetrachloride and rfAyt alcohol bp vfomeeb tube J. Trirhlomaphthalme plut trace of trtrachlornephlMene. Fed at 9:00 a.m., Nov. 10,1930. 10 raU. No deaths. 3. renta and fcrroeMomophttaJsRss. Fed at 9:30 a.m., Nov. 10,1939. 10 t*U. 8 died Nov. llth between 4:80 and 10:30 p.m. 1 died Nov. 12th at 3:20 p.m. 1 died Nov. 12th at 4:30 p.m. 1 died Nov. 13th between 9:80 and 11:80 a.m. 1 diod Nov. 10th between night of Nov. 14th and 12:30 p.m. Nov. 10th. 2 died Nov. 19th between 10:10 p.m. Nov. 19th and 9:00 a.m. Nov. 16th (sUlf). 3. 90 per cent penta and hexachlomaphthalenee and 10 per cent chlorinated diphenyl. Fed at 10:00 a.m., Nor. 10, 1989. 10 rate. 1 died Nov. 10th between 0:00 and 10:30 p.m. $ diod Nov. llth between 4:30 and 10:30 p.m. 1 died Nov. llth between 4:30 p.m. and 9:00 a.m. Nov. 12th. 2 died Nov. 12th about 1:00 a.m. 1 died Nnv. 13th botween 5:00 and 10:00 p.m. 4. Chlorinated diphenyl. Fed at 10 00 a.m., Nov. 10, 1936. 10 rats. 1 killed Nov. lOtb at 10:30 p.m. (almost dead). 2 diod Nov. llth between 4:30 and 10:30 p.m. I died Nov. 12th before 8:30 a.m. (stiff). I died Nov. 13th between 9:30 and 11:00 a.m. 1 died Nov. 16th between 10:15 p.m. Nov. 15th and 9:00 a.m. Nov. 16th (stiff). Controh: Fed at 0:30 a.m., Nov. 12, 1930. 10rata. 1 killed Nov. 13th lor normal liver. Tins tabulation summarizes into the. facts that: 1. No normal rats wctc killed by carbon tetrachloride and ethyl alcohol. 2. No trichlornaphthaicne. exposed rats were killed, and this finding agrees with our inability to find lesions of moment in the livers of the animals (bat inhaled this substance. 3. The penta and hcxachlorinatcd naphthalene, the mixture of these with 10 per cent chlorinated diphenyl, and finally the latter substance alone seem to have produced conditions lowering the resistance to an agent capable of producing serious liver disease. 4. The sole lesion produced by this test of liver function was acute yellow atrophy usually accompanied by jaundice. This test of liver function was ac complished with a substance which itself is an organic chloride and curi ously enough it is the only substonoe we were able to find that was effective. ! i I i HONS 09736S 'lAXljfrU. 294 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY |5pL I9ST In animals with the minor degree of liver injury which has been described wc were unable to produce acute yellow Atrophy or any variety of liver effect with arsphcnaminc, cincophen, butyl chloride, ethylene chloride and tetrachlorethylenc, 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 tctrachlonmphthalciio being practically normal on removal from exposure need no consideration. In the ease of the penta and hexachlor- signa of liver injury will be many months in returning to normal. The effect of high concentrations of trichlomaphtiiaknet with traces of Ictrachlomaphthalenc,--The first group of inhalation experiments showed that this material in concentrations averag ing 1.31 mgm. per cu. m. of air was relatively innocuous, judged both by direct observation and by the carbon tetrachloride test. This is an in teresting fact since such compounds cause acne, though less potently than substances of higher chlorination. In order to explore the matter further one of the inhalation boxes was arranged TABLE 2 Conditions Maintained domino Inhalation or High C oncxntb ationa or TaiCIILOSNArHTnALBNES PLUS TETnACItLOnKArilTITALSNE MAMMAL Mur. AT. COKCBWTRATIOH or Alt IN sox TOTAL AT. BAM.T iinuit XtOOUM Triclitortmphthalcnei plus (races of lotracMornaphllialcne c. Mf./C*. 137-200 10 97 ran# High 10 49 Low 5 78 Iftri 1232 low* 16 naphthalene, rats after 2 months' re moval from exposure still showed swollen liver cells, increased granu larity, hyalinisation and mitotic fig ures. The condition was not advanced aa compared with rats killed at the time of removal from exposure but on the other hand 2 months were insuffi cient for recovery. The same findinp were true of the mixture of penta and hcxachlorinatcd 'naphthalenes and chlorinated diphenyl and for chlorinated diphenyl alone. Apparently the changes induced in tlie liver cells by these substances are exceedingly persistent and one must expect that an individual showing any so that fumes from four glass contain ers were delivered to the air line instead of one. This resulted in the conditions shown in table 2. The animals sub jected to these conditions showed no clinical effects of any sort. After 1 month the liver cells were slightly swollen and over-granular and there were occasional mitotic figures. 'These changes were similar to the early effects of more highly chlorinated compounds, and progressed only slightly during the third and fourth months. When rats in this condition were given carbon tetrachloride and alcohol, in some instances their livers showed massive central necrosis and in r rats one chit tov the; upo trat 1 pen TM sge but pur coti not Con Pun atre u.-c On sub mar WON the and surf tlrrt for kith and exp Irillt fitO wiftt ante HONS 097369 ref. 19, no. 7] EFFECT8 OF CHLORINATED HYDROCARBONS 296 in others tliis did not develop. Fifty rats were used in this exjwriincnl and one may conclude that while the trichlomaphthalcncs arc in no degree as toxic as those of higher clilorination 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 nud hexachlomaphthalcne*.-- There enn be no doubt ns to the dam age done (lie 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 hoxachlornaphtlmlcnes arc markedly toxic com|>ounds and that recovery from their effects ia extremely slow. The effect* of penta and hexacklornaphthalcncs, the mixture of these with tO per cent chlorinated diphenyl, and of chlorinated diphenyl atone, when inhaled in low concentration* through an 8-hour day instead of a 16-hour day as in the first experiment.--Since steady human exposure to any of the compounds tested would invariably be for 8 hours rather than lG-hour periods, a further TABLE 3 Condition'* Maintained dcki.vg Inhalation or Hum Concentration!* or Tcnta and llEXACnLORNArilTtlAUCMEt imiiu -- AT. COKCBKTriATIOH or AIK IM ox TOTAL IXNIlIt c. mf./ctt. Fonta and hrxaclilomnplithaletica......... 137-195 8 88 unf* High 14.0 Low 5.75 l,vr, 608 atrophy occurred except through the use of the carbon tetrachloride test. On Dorcmbcr 1, 1936, 80 rats were subjected to the conditions sum marised in table 3. This experment was terminated on January 21. Ail of tlsc animals lost weight and appetite and deaths began after 8 days of expo sure. Fifty-five rats died, most of them heavily jaundiced, 8 were killed for microscopic examination, 9 were killed by the carbon tetrachloride test and 8 lived through the period of exposure. Tho livers of the animals killed for examination showed marked fatty degeneration, central in type with necrosis of liver cells. Surviving animals showed pronounced changes in inhalation experiment was arranged under the conditions shown in table 4 which are quite comparable to those in table 1 except for the shorter inhala tion periods. Eighty rats were used for each of the three compounds tested. None at any time showed the slightest evidence of illness. Microscopic ex amination beginning after 6 weeks' exposure showed swollen liver cells, excess granulation, hyaline inclusions and occasional mitotic figures. These changes did not progress and were very similar to those in the animals exposed for 16 hours under the conditions set forth in table 1. The carbon tetra chloride test was uniformly fatal to them and one must conclude that con- i LV 290 JOURNAL OP INDUSTRIAL HYGIENE AND TOXICOLOGY I9S7 ccntrations of these compoundR such oa were employed cause a certain de gree of liver damage even if inhaled for but 8 hours daily. This injury is resisted successfully by the rats just as was the 16-hour injury but it is none the lesR there nnd destroys the ability of the animal to resist the carbon tetrachloride test. Summary of inhalation experiments. The findings that have been described briefly will be amplified upon the pathological side in a further paper by Dr. G. A. Bennett. What has been given is, however, sufficient to indi men never inhale enough of any of these substances to get acute yellow atrophy. They may, however, acquire a substratum of liver damage upon which acute yellow atrophy may de velop. Experience in a number of plants has shown how easy it is to reduce concentrations of these com pounds practically to the vnnidimg point, and every effort should be made to attain such conditions. Cross Feeding Experiments The various compounds used were ground as finely as possible and mixed with a standard balanced ration for TABLE 4 Conditions Maintained dpiunq Inualation or Low Concentrations or Three CoxrooKDS ddrino 8-!1oor Instead or 10-Hocr Periods ttiniuu Tsar. AY.oCrOANISCIIXNTIMAYIlOH tlFTOOATAt'LMi uA*r.oUiAi'IHLT c. nfm./.ru. Penta and hoxaohlornapbtbalenef........ 146-103 1 44 60% penis nod bexaehlornepbthatenee plus 10% chlorinated diphenyl........... 150-107 1.60 Chlorinated diphenyl............................... 153-174 0.03 wife High 2.68 Low 0.42 High 3 80 Low 0.6G High 3 23 Low 0.03 Aw* 020 012 020 lIV| 8 8 cate that compounds more highly chlorinated than trichlornaphthalene are capable of causing liver injury when inhaled steadily in quite low concentrations. It is an extraordinary thing that even the most searching examination fails to show injury in any other region. It is not easy to grade the toxicity of the different compounds tested, but the clilorinatcd diphenyl is certainly capable of doing harmin very low concentrations and is probably the most dangerous. Industrial experi ence combined with these experiments make it appear probable that work the white rat. The food was placed in a single container, at which the 10 animals in a cage bad an equal chance, tho amount of the compounds added being reduced as the number of rids lessened during the feeding period. The experiments were designed to give an idea as to the possible toxicity of the compounds selected and, if toxicity was observed, some idea as to the site or aites of damage. The experiments were successful in both respects, and indeed one may anticipate that future appraisals of the possible toxicity of chlorinated hydro- vol. 19. carboi feedir rale a wiry J eMcn in tin by be differ si'Pin so fa I'vrr Tr tclrae on I until ning to 1l and t throi nnim w hie loss wat dent Npirn tion 11 digh of gi 7*Frci dov Ain wen 29, A logi nffe* *, siou Hum wa? / Fee doa MQNS 097371 1887 ny of tvllow 'quire upon \y do* ,i i of tO pom* jolting made were mixed ,ou for IRXR I % I placed the 10 chance, - added of rain period. . io |ive I .icily of toxicity the site stful in up may .1* of the i hydro- Pot. J8, no 7) EFFECTS OF CHLORINATED HYDROCARBONS 297 carbons mny often be made by simple fording and do not require the elabo rate apparatus and the expense neces sary for inhalation experiments. The essential reason for thin opinion resides in Uic identity of the lesions produced by both methods, and the fact that the different compounds so far studied seem to arrange themselves identically so far as toxicity is concerned which ever way they art* administered. Tric.hlornaphthalc.ne plus traces of (ctrachlornaphthalcnc.--Vcxdmg began on May 4, 1930 and continued until November 2,1936. In the begin ning 3 gm. of tins mixture were added to the food for 10 rata each day, and this concentration was maintained throughout the experiment. All the animuls were killed except the last which died on Nov. 2. There was no loss of weight and no appearance of wasting illness of any sort. The single dcftlli was due to some variety of re spiratory infection which had no rela tion to the mnterinl inhaled. Histological examination showed slight changes in the liver but nothing of great significance. Tctra and pcnlachlornaphlhakncs.-- Feeding began on June 29, 1936. A dosngc of 0.5 gm. daily was employed. All the animals sickened gradually and were cither killed or died by August 29, 1936. At autopsy both grossly and histo logically the liver was the single organ affected. The liver ceils showed swell ing, hypcrgranulation, hyaline indusions and vacuolation. Here and t here necrotic cells were found. There was a tremendous accumulation of fat. Penia and hexachlomaphthalenes Feeding began May 4, 1936, a 3 gm. dosage being used. By June 6, nine rats had died. The last one was obvi ously ill and was killed for autopsy examination. All animals lost weight from the beginning nml were ill. At autopsy the liver alone was affected, the lesions observed being similar to those that have been described for telra and pentaehlornaphtlmlenos but worse. 90 per cctU penia and kcxachlornaphthalenes and 10 per cent chlorinated diphenyl.--Feeding began May 4, 1936 on a 3 gm. dosage. On May 16th feeding was stopped but all the animals went on to death, the last dying on June 8th. An autopsy the liver lesions were extremely severe and of the usual type. On account of the high toxicity of the 3 gm. dosage, four rnts were given a0.5 gm. dose every other day. Feed ing began June 24, 1936 and the last animal wns killed Sept. 11th. There were no deaths but nli the animals lost weight. At autopsy the liver as usual was the single organ nfleeted, the lesions being characteristic and ex tensive. Chlorinated diphenyl.--Feeding be gan May 4, 1936 on a 3 gm. dosage and was discontinued on Mny 10th. Seven of the 10 rats were dead by May 12lh. The three remaining rats gained in weight but were sacrificed for autopsy purposes on July 8th. The liver changes began at once. There were no changes in other organs. A second group of 10 rats was fed a much smaller dose--0.5 gm. every other day. Feeding began May 20, 1936. The first rat died on May 29th and four more before June 24th. The remaining were sacrificed. Those rats that died showed losses io weight, while those sacrificed had recovered l I | I ! i AGNS 09 73 72 298 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY 1Sept, t887 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 hexachlomaphthalenes 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 Summery of groee fading experi ment.---Of the various materials fed rats in large doses triehlornaphthalene the liver was the sole organ affected and the lesions were those already described many times. plus (races of tetrachloroaphthalenc DtflCOSStON' was quite innocuous. Tetra and pent achlornnphthalcnc showed definite liver damage. Renta and hcxachlorunphlhalcnc* caused a similar grade of injury. The addition of chlorinated diphunyl to penta and hexachlomaphthidcncs increased (he toxicity. Chlo rinated diphenyl alone produced liver lesions but in the dosage used was less "effective than when mixed with highly chlorinated naphthalene**. In no case did (hr 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 |>eriod of time. These experiments leave no doubt aa to (he possibility of systemic effects from the chlorinated naphthalenes and chlorinated diphenyl. As in the case of the effects upon the skin, the degree of chlorination seems to determine the systemic toxicity, and it is a striking thing that when tridilonmplithnlenc is reached systemic effects arc never marked and arc produced with the greatest difficulty. It is most u-iuorkable, 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 Dose* 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 aNsuining an air concentration of 20 mgm. per cu. m. was first calculated and reduced to milligrams per kilo gram. The rata and rabbits received this dose each day. The compounds used were thoee employed in the gross feeding experiments and the results were essentially similar though the lesions were less severe. mals very severely poisoned by penta and hexaclilornaphtbalencs but have found no increase over norma! figures, though the livers, as determined histo logically, were very severely affected. At the present time 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 tctrachlomaphthalene. We are also determining the degree to which the diet may increase or decrease toxicity, Subcutaneous Injection* this being suggested by similar work The same gum acacia suspensions upon carbon tetrachloride. were injected subcutaneously into rats In the baas of these experiment* MQNS i 097373 wJ. /. and oi differ** room* tainly that t more t of tilt napht comix are ninny plant1 been 20 ye fact been liuma Time cha| but t safe. hi rati hydw safe* lend Covm r t ( A P Fun I* $ Lem A IW oil- on* liU TOW .Ur ted r.lly .ubt -cl# Mid CftP :*mt thfl ;ing i# ver ilw :.ukmd# iim :<ih# cully 9111*nta imvc ire#, iblOited. cliug orinccnt .tl M orted with i and alto h the work titrate vol. If, no. 7] EFFECTS OF CHLORINATED HYDROCARBONS 299 and on many field determination# 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 docs not contain more than 0.5 mgm. per cu. nt. of any of these compounds above Irichlornaphthalenc. In the case of the latter corn)>ound concent rot ions oflO.O mgm. are permissible. We know from many examinations in many* different plants that such concent rations 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 oxj>o?ure is never #o ordered. Time and careful observation may change these opinions as to standards, but today we are convinced they arc safe. Impregnating tanks and other arrangements utilising the chlorinated hydrocarbons arc cos}' to hood and to safeguard. Compared with benxenc, lead tetraethyl and many other com- pounds, these substance# are very little toxic and operations employing them can easily be safeguarded. K may be argued that where possible tricldornaphthalcne should be used, but this compound will cause acne and if employed verj' carelessly might do more. Furthermore, higher chlorina tion is often essential for highly prac tical reasons. The solution consists in thoroughly adequate ventilation plus good housekeeping around all wax containers. A'final word of caution bears upon the use of carbon tetrachloride as a wax solvent. Obviously this comixnmd adds readily to the toxicity of the highly chlorinated waxes. Jf carbon tetrachloride is used, ventilation should be excellent, but in our opinion it would be belter to dispense with car bon tetrachloride and depend on other solvents, especially upon those con taining no chlorine. BIBLIOGRAPHY CocRTOifl-ScrriT: Etude sur I'lntoxication profcsaiomielle par le trichloronaphlalftnc. Ami. de m6d. Idgale, /{, 423 (193-1). Abslr. of paper by Tocraine, A., and Mntrcl, B.: Dermatoses profcssionnclles par la naphtalme et itea derives. Prat. mtd. Iran?., IS, 835 (1934). Funk, F. B., and Jantje, X. E.: Action of certain chlorinated naphthalene* on the liver. Proc. Soc. Exper. Biol. A Med., 35, 118 (1930). Lehmann, K. B.: Ktirses Lehrbuch der Arbeit*- und Gcwerbehygieno. S. Ilirtel, Leipiig, 1919 (p. 251). MiTTBLSTiDT, 0.: CcwerbesclmdiRiiPRen durch Units* (Trielilornnphthalin). Insug. dissert., Jena, 1935. Tbbbens, B. D.: Portable combustioo ap paratus for field determination* of chlorinated hydrocarbons. Tins J., 19, 201 (1937). Tblbxt, L.: Die Pernakrankbeit (Chloracne). Klin. Wehnaehr., 9, 897 (1927). Touraine, A., Solente, Mxtrri,, 13., and Avftntm: Cinquante-quatre css de dermatitea par trichloronaphtaline. Bull. Soc. dermat. et syph., 41, 265 (1934). MQNS 09 73 74 300 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [Sspf. 19S7 Discussion Da. Cecil* K. Drinker: We have had quite a long morning, but eince Dr. von OetUngon has to leave, I am going to ask him to aay a word. Dr. W. F. von Octtikqsn (Director, Ifaakell Laboratory of Industrial Toxicol ogy, Wilmington, Delaware): I wish to con gratulate Dr. Drinker and his group on the very interesting and excellent work on the subject. 1 eleo wish to congratulate the Halowax Corporation on the fact Umt they didn't spare any effort to ducide tc the prob lem so that the dangers which apparently arc connected with the use of Ibis material ran be controlled. I personally believe that there is no toxic material which cannot be used safely if it is handled properly. In order to handle such materials properly during the different oper ation* it is absolutely essential to be famil iar with the toxicity nod es|>ecinHy with the mrrhanirm of the action. Since there is no animal wldeli rorrei>|*onds in all its physio logical characteristics to the human being It is important (hat such compounds be studied with different species of animals so (hat one ran get a cross-sectinn of the poten tial dangers. In addition, this fart illustrates the im portance of thr pre-employment and peri odical examination of workers In such work. As was pointed out by. Dr. Drinker, there are individuals who are apparently more ueccptible to certain toxio agents than others. On the other band, we have to try to detect tho very first signs of incipient poisoning in order to prevent more eerious damage. In the present instance it is very difficult to find (hero very first symptom* because there arc no adequate methods, but I trust that in time the scientific profession will supply the medical profession with adequate methods which will allow the physician to determine incipient damage of the organ before eerioue clinical symptoms become raauifaat. Thank you. Afitmoon Session Dn. Cncu. K. Drinkcr: In this discus sion I will call on ooe or two individuals and I shall oxpoct othora to apeak as their ootea incline them to. First of all I shall ask Dr. Sayera if he will open tho discussion for us. Da, R. R. Sxttm (Chief, Division of Industrial Hygiene, National Institute of Health, U. 8. Public Health Service, Wash ington, D. C ): Dr. Drinker, Ladioa and Gentlemen: It gave me a great deal of pleas ure to have the opportunity to listen to the excellent and interesting discussion and presentations made this morning. Dr. Drinker, and 1 might add, the members of the Halowax Corporation, have discussed this matter with us, as well as the manu facturers of the diphenyls.' Wo have been doing some work but not nearly as extensive as (hot carried on hero. The work that we have been doing seems to confirm the work that Dr. Drinker has car ried on. I think there are certain parts of it that we ran very well keep In mind. We sic dealing with toxic substances, but we are dealing with toxic substances each and every day in industry--harmful sub stances, hasardous substances. That these can be controlled is well known, no matter what they are, and that we can use them and use them in a safe manner. Dr. Drinker has called your attention to the fact that this apparently has been done and can be done in any of the plants where halowax is used. I have information from one or two of the other men who arc in the audience that in plants where damage has been done -- akin damage and apparently liver damage to some of the workers--the manufacturers have since corrected (lie conditions and ap parently have adequato engineering con trol supplemented with adequate medical control. After all, the proof of the pudding is in the eating. If the man doea not get the dis ease your engineering control is successful. If he does get the disease, no matter what you have done in the way of engineering, you haven't been succeasfu). We must go band In hand. Neither profession alone cao be aucceasful. We have got to work togethar whether we like it or not. 1 hap pen to like it. There is one other thiog. As far as mate rials are concerned I think we ought to b* vol. /*, * mart mo fcssfully. adapted f. *t. A not} vinue t<> u ** flnmni I'pruxiuM, ay appro, never just it might ha ere unite. happened % *th thin lectric mg armor th. *'d ums bi*h Pfoximettl) to a Kti-fJ rr bottom nfth, inspecting it bide rap-inn, tho fire hij|fC m. Many Here w *. Now we haw due lu me t evaluate then, 1 *m informer nn1 just iu,,, flammability chlorination ir l"o increase* creases, acnnrr think that t U have the-c lllu control t!ltllli we can. present tin.' better. I a, submarine*, ftoft-flarntae). of their elect Da. Ctct you care to t Dn. / of Or^u necti'ut Conr..;; any tbi.., this n.kl< 'VRS ! I MQNS 097375 toft. 1997 I iib)l Mk r'leeoeaion vision of ititute of in., Wtsbadlet tod .iofplsaaten to the m4o* end in*. Dr. embers of diseuaeed the mono- k but not rl on here. KMomito n hM earpartaofH :td. -.-mres, but nines each -mful eubThot theeo no raotter e them and r. Drinker ? feet thet md en be lietores it not or two :.e audience been done vtt damage .ufaeturcrs nii end a|>rring eon* -at medical tddfog la in net the die* eneoeeeful. `netter whet "ngineerlnf, Ve meet go 'ion elone -ut to work not. I hep- fereemetoougbt to bo t "i*n eel. 19, no. 7} EFFECTS OF CHLORINATED HYDROCARBONS 301 mart enough to uee every one of them aucoeeefuUy. If thie materia! ie particularly adapted for a certain purpose we abould uee it. Another materia! that wee used pre vious to this for insulation purposes, which was flammable, caused a disaster in which approximately 187 men lost their lives. I say approximately J07 because they were never just sure whether it was 107 or 168. Itmight have been one or two more but they were quite sure that 107 lost their lives. It happened when they had insulated a cable with this material. They had an armored electrio cable. It w-aa covered with lead armor on the outaide. It waa 1200 feet long and waa boing lowered into a mine shaft ap proximately 3000 feet deep. It was lashed to a steel rope. It slipped and fell to the bottom of the shaft. When the foreman was inspecting it be eet it on fire with his carhide cap-lamp. The carbon monoxide from the fire killed tboso men that were in that mine. Many of course escaped. Here we have one hasard, a fire hazard. Now we have another one, a health hasard duo to the toxic materials. We have to evaluate them. Certain of these materials, I am informed, are also flammable. I am not'just sure how flammable they are but flammability probably decreases aa your chlorination Increases. But your toxicity also increases as your chlorination in creases, according to Dr. Drinker, and I think that checks with other findings. We have these hazards to balance but we can control them. I feel quite confident that we ean. Ferhaps we can find other substances that are better even than this material. At the present time I ain advised thet we have no better. ] am advised that in ahipt, such as submarines, it is quit* important to have a non-flammable substance for the insulation of their eleetrical wire. Dn. Cecil K, Drinker: Dr. Gray, would you care to say a word? Dn. Albert 8. Gray (Director, Bureau of Occupational Diseases, State of Con necticut Department of Health, Hartford, Conn.): Dr. Drinker, I don't think there is anything that I ean say except that we used this material In Connecticut and we had a number of so-called cases. All 1 ean say ii a confession of ignoranco on our part at that time and I was very glad to seo that your digging into the literature aa thoroughly as you have hasn't eiicitod any further infor mation than we were able to get, basically. About all wc could find was about the two cats that our friend, Lehmann, experi mented with. Wc got in touch with him and he oonfeesed that the amount that he had given the cats and bis method of determioing it were probably subject to very serious scientific criticism, and we agreed with him on that point. We felt, and 1 am very glad that it is what you feci 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 it what we did entirely empirically. I think that is about all 1 have to say. I have been delighted to be here and to have as many members of my staff here as 1 could jack out of the office. We have been de lighted to listen to tho discussion. Dn. Cecil K. Drinker: May we oow make the discussion general and those who have questions please volunteer. Mr. Manfred Bowoitcu (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 Vo the approach to this problem in proper control rather than by prohibition, which teems to me wholly unnecessary not only in this case but in the rase of other toxie substances with which we have to deal. The problem of proper ventilation seems to me relatively simple from what 1 have beard of the situation thua far. The problem of maintaining that ventilation properly does not seem to ine quite so simple. I think it is going to be quite necessary that there should be a very adequate inspection of the plants using the materials and I can assure you that that will be the case here in Massachusetts. When this trouble first broke in this state a little over a year ago w*e issued a quite strongly worded warning letter to all plants ruing these substances and it hat all along MGNS 097376 f V 302 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY {Stpl. 1937 been my plan to follow that up with a furlhr letter bringing the situation as we now know it, aa a result of Dr. Drinker's work, to the attention of users in this state. In that letter we shall unquestionably advo cate the concentrations that Dr. Drinker has suggested this morning. One point that I think is worth comment ing on in that connection is the question of identification of the substances. It is ex tremely important from the state adminis trative point of view that employers using these substances should know what they are using. They are identified at present only by numbers. If we list those numbers in a warning letter which we send out there are likely to he ebanges in those numbers. The Halowax Corporation it a progressive coucem and it is going to be putting out bigger and better halowaxcs all the time. The company's cooperation in this present inves tigation has been euch that 1 feet assured that they will lake the proper steps to see that we in the state offices and also the users of the products will know whet we are using. 1 wonder whether Mr. Brown would care to say anything about that. Mr. BANnronn Brown (President, Halowax Corporation, New York, N. Y.); There are some aspects of this situation on which J 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 Urge chemical manufacturing company today you will find anything from one to a thousand different new chemical products which have not yet been put on tbe 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 thie morning by the Drinker brothers as to the work that they have done here. Should you take a product of which you have developed, say, 5 or 20 gm. and spend $50,000 on research to determine whether or uot 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 number* In the way of dollars sad cents before you ever sold any. That is the problem we have had in this case. It has been on the market for 25 years. Until within the past 4 or 6 years there has never been any intimation that it would cause %ny systemic effect*. Thou sands and thousands of workmen have dealt with millions and millions of pounds of cer tain of these materials, particularly the trichiornaplithalcnce. Then we come to the higher singes, combined with chloi mated diphenyl and other products, and suddenly this problem is presented to us. We had asked various authorities in terested in publir 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 wc take it up with the Drinker brothers at this institu tion, which we did. You know the results of that work. Now' so far as these changes arc con cerned, they arc beyond our control to a certain extent. We will manufacture a product--let's call it 1231. It has certain chemical and physical characteristics. It is supplied to a cable manufacturer. It is composed of certain constituent*,. There may be some tctrarblornaphlhnlcne, triehlornapbtholcne, paraffin, a little pitch or bitumen, and possibly some chlorinated diphenyl. It does a certain job but he wants it to n little more plastic or he wants its viscosity or tbe specific gravity changed. Possibly by a change in those constituents of only 1 per cent we can get that particular property. Wc 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 uf that will not change. When it comes to a question of cooperat ing with the state authorities in that con nection, if there were some major change made in a product we w*ould have no hesitaney in advising them and we would also advise our customer*. 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, whethor they be physical or chemical. Thoso are some of the practical problems -T,---W MQNS 097377 I ml. If, we. 71 EFFECTS OF CHLORINATED HYDROCARBONS 303 with which alt manufacturers of chemicals wr confronted today, particularly in tbs synthetic organic field where the develop ment la eo rapid that our ealca department! can't even keep up with the research departmeuta aoinotiinee, in knowing what they are doing. Ml. F. R. Kaimbr (Aeeietant to Man ager, York Wireworke, General Electric Co., York, Pa.): 1 am certainly pleaeed to have tide opportunity to say a few words with reference to the experience we have had at our York plant. 1 perhaps should eay that again in thia caae experience alone has been the best teacher. I have lived with the problem at York with the men who went through the experience from ite beginning. It is only l| years ago that we had in the neighborhood of 50 to 00 men afflicted with varioua degrees of thU aene about which you all know. Eight or ten of them were very severely afflicted--horrible specimen! aa far at their skin condition was concerned. One mnn died and the diagnosis may have attrib uted hie death to exposure to halowax vapora hut we aro not sure of that. There wan an atrophied condition found as a result of the autopsy but we are not definitely sure Ihnt it was or wan not connected with Ilia work. Knowing the man aa I did when he was employed, with the superficial examina tion that he had, he appeared to me very thin, pallid in hie appearanro, and 1 would not say from my poor knowledge of the physical make-up ot the human being that he presented a healthy appearance. How ever, it was only for a 0 months' period from the time of hie employment that be com plained of thia conatipatod condition and we advised that ha set his home physician. H rapidly developed to Ihe point where he was in the hospital and in a vary abort time he dlod. More serious than that perhaps is the fact that we had 00 other men in very bad condi tion aa tor as tha aene was concerned. The first reaction that several of our executives had waa to throw it out- get it out of our plant. They didn't want anything like that for treating wire. But that was easily aid but not eo easily done. We might just as well have thrown our buiioeae to the four winds and said, '`We'll close up," because there was no substitute and there is none today in spite of all the efforts wc have mado through our own resoareh 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 PeppcT ol the University oi Pennsylvania Hospital, and the others to Dr. Isaac R. Pels at Johns llopkins. Through their recommendations and studies we employed a trained nurse and two local physicians and you might say established a mall hospital and its facilities at the plant. Through the applirstion of quarts light, x-ray, mechanical removal of comedones and the treatment of pustules that de veloped in later stages, an utterly strict routine where the worst caeca 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 ibis year and a half brought each and every man back to a normal skin condition. Those who were very scriouxly afflicted do show Bears, but otherwise their skin is at healthy in apiwaranee aa my own. I tell you wc arc 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 havs metalled, with the routino for change of clothing from street clothing to work elothing when they come to work and the reverse of that process, with the assurance that a shower will be taken before the street elothing is again put on, we have found no recurrence of thia skin trouble. Koch and every man working with halowax products, either from solution, from solid compounds or handling the wire insulated and treated with U, isexamined twice yearly with a com plete physical examination, including blood analysis and efforts to determine any liver damage. However, there is the point which waa very definitely brought out this morning. We do not know as yet when this thing starts. I bolieve it would be of great help 304 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY ISepi. 1997 to us all In industry it tom* very funda mental work wu done on human*, aa Dr. Jones mentioned before we came into thla mcetin(, eoroc control iu fundamental work to determine tome method whereby we may determine the inception of any liver dis order. We have had our men examined in groups three times since the trouble developed and nothing has shown up in any one man. We have learned and appreciate the fact that we must handle hazardous materials, but we have learned bow to handle them. It has been a very great experience for ua and for myself, and again the best teacher. Dn. Cecil K. Drinker: Can you recol lect the air concentration that you are main taining now with your present ventilating equipment? Mn. F. R. Kaimer: We have bad two examinations made of the air by Mr. Wil liam F. liemperly and they average from0.2 to 0.6 mgm. per cu. m. We recently dis covered one condition which was found as the cauee of a high reading in one of the examinations. The compound is one that is not manufactured by the lialowax Cor poration that is used rather infrequently, perhaps not more than 60 gailone of it in a 0 month period. It is in the form of a paste, reduced with solvent to a pasts form, and it was not known that it contained a chlorin ated solvent in certain percentage. We dis covered it only recently through the analy sis of a sample and we found that that was the cause of throwing the results off to a high value. Itwaatbenabuutgmgm.pereu.m., 1 believe. That is going to be eliminated now. That la a combination of toluene and earbon tetrachloride solvent. When that compound is exposed to the air the chlorin ated solvent odor is completely masked by tiistoluene. It is lost. 1 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 eeoonds tbe tolu ene predominated and we had ao knowledge of the other being in there. Ma. AiTBua G Baras (Research Engi neer, United American Roach Corporation, Springfield, Moss.): Do I understand you to say that those men wbo were afflicted are back on the same job? Ma. F. R. Kaimer: They all returned to normal skin health, aa I aay, and are work ing on the same job. Da. Ckcu, K. Drinker: Dr. Schwarts, you have seen a good deal of thin general subject. Dn. Louis Schwarts (Mediral Director, Dermatoses Investigations, United Btatcs Public Health Service, Now York, X.Y.): 1 am primarily interested in dermatitis end it waa only because of my researches in that field that 1 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. 1 can only talk from personal experience about the skiu eases. 1 know from whet 1 have seen and from what I have heard from doctors who have been treating these cases that if they are treated like au ordinary acne vulgaria and kept away from further large exposure they all get well, with the same results as acne vulgaria. Those who have large pus tules may have scars resulting and those who have superficial pustules or only come dones won't have any scam. As far as prevention goes, I felt even be fore this investigation waa undertaken that this substance, like any other poisonous substance, can be handled end used in in dustry provided proper safety precautions are taken, end I so advocated at the meeting is Pennsylvania when this was discussed. About ventilation end safely precau tions, 1 think that while we cannot, with our present knowledge, detect by any chemical tests the early symptoms of intoxication from this substance, tbe skin offers an easy way of proving whether your method of Ventilation is efficient or not. If there are any eases of aene or of this dermatitis occur ring in a plaut where halowax or the chlorin ated naphthalene or chlorinated diphenyls are used, then that shows that there la suf ficient concentration of these substances in the air to cause plugging of tbe follicles end to eause a skin condition. If there is suffi cient eoneentration to do that there aaey be HONS 097379 mask .jV-Jll tel. 19, no. r\ EFFECTS OF CHLORINATED HYDROCARBONS 305 sufficient concentration to cause systemic poisoning in tlio fr people who art* hyper sensitive to the action o{ these hydrocar' bona. Everybody is not hypersensitive to them. If they were, of the thousands of people who have boon handling tbeae 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 sa 1014 or 1915. While I cannot add anything to the methoda outlined here for eafety In the way1 of ventilation and ao forth, I can say that If you go into a plant end find thet there ie any acne present among the workers with thin materiel you will know that there ie sufficient of the substance in the air to cause acne and consequently sufficient perhaps to be dangerous to tiie few j>eople who are hypersensitive to its action. lift. Cecil K. Dhinkkr: 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 c arc in a position of learning, that we endeavor, if we ean, to confine our analyses to one piece of appa ratus, so that at least our results will be as comparable as we ran 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. Ma. 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 balowax I wonder if it wouldn't be preferable to have Mr. Hemperly discuss the method be has been using throughout the country for the determina tion of chlorinated naphthalenes. I>r. Cecil K. Drinker: I think to far as that is concerned it is best to leave that to discussions with Mr. Hem|>erly and Dr. Brandt afterward. But the question of determining tome uniformity of technio for n while at least is, 1 think, a matter of gen eral interest to us. Mr. Warren A. Cook: I am not quite sure (hat I have in mind exactly what you want in that regard. In connection with sampling? Dr. Cncin K. Dkinxer: Yes, In con nection with the whole technic of determin ing the material in air, length of sampling, type of apparatus, and so forth. It has been suggested that we endeavor to agreo 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, wo will at least have them on a comparable basis. Mn. Warren A. Cook: In (hat 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 expei imentation. In order to obtain data which are of value along that line it is desirable to know to what extent, in terms of milligrams pec cubic meter, workers are exposed Vo in breathing any potentially injurious material. It seems to me that one of the things that should be done, which many of the plants and many of the organizations equipped to make determinations of injurious materials in air should do, is to make an effort to develop one group and serins of results which will represent average exposures of workers to chlorinated naphthalenes. In getting that figure I think that it is of great importanre that w e 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 30 minute period when the worker may be actually tending a pot where the material is being used, whereas during the subsequent half hour he may be 40 or 80 feet away from that particular location. Therefore, (or one thing, it seeme to me it would be extremely desirable to obtain in formation iu as many plants and as many loeationa as possible of the average expo sure, taking into consideration uot only the worker's maximum exposure while actually HONS 097380 I 306 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY (S,pl. IIS7 i at work with thee* materials but also hia before the A. F. H. A. in October a* one of much smaller exposure and possibly even the projects which we shall carry out at i lack of exposure as he may go to other parts of the room or even to other department* during tbe courso of the day. that tirao. As I have not given this consideration, I am afraid my discussion is not aa connected Another type of determination which aa I might wish it to be. We have a reel seems to be extremely desirable to have is problem berc and one that deserves some concentrations o( the chlorinated naph study. thalenes at certain reference points. I believe that Mr. Hemperly very carefully Dn. Cecil K. Drikxck: Would it he of duplicated these reference points in eseh service to the American Public Health Asso of tbe plants whero he took his determina ciation Committee if s sub-committee from tions. lie look the samples, I believe, at this meeting, collected perhaps hy my breathing level arid a certain measured dis brother and those of you involved with these tance from the pots where the chlorjnsted problems, were to make a recommendation naphthalenes were being handled, so that to the A. P. H. A. as to the tilings 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 at those same locations, which are Association after they have considered that definitely fixed sod recorded, and learn material? i whether, due perhaps to clogged pipe lines or to fane which might become loadod with Mb. Waubsx A. Cook: I think that 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. A 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 sn ex which wc have here and also (he continuous tremely dcsiiable thing to hare 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 at one plaut or at another, a considerable group could give that committee a very group o( workers could be taking samples at definite steer. this one particular point with reference to [Personnel of the Bub-committee: W. A. the source of generation of the vapor. Such Cook, chairman, A. I,. Coleman, H. 0. El results would permit a comparison of knowl kins, W. B. Fulton, S. W. Gurney, E. R. edge between plant*. Hayhurst, W. F. Hemperly, F. W. 8ebl, and In that regard it happens that there is a A. N. Sclterlind.) committee of the American Publio Health Association w hich is charged with tbe devel Mr. Hrrvst 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. U seems to tries, Boston, Maas.): In connection with me that it might be a very desirable project what Dr. Schwartz has said, I am not sure for that committee to consult with the in that 1 am in complete agreement aa regards vestigator of tbe Halowax Corporation and the use o! skin lesions as waroing scents. suggest to sll of those who are doing work It ia my understanding that in insulated of this type, after some discussion, what wire plant# the chlorinated diphenyls are reference points could be adopted and also very commonly compounded with the chlo w bat should be done in connection with get rinated naphthalenes. It is also ay under ting these average exposures. Asamitter standing that these are more likely to cause of fact our committee will discus* that very a severe skin irritation than the straight feature and possibly include it in our report chlorinated naphthalenes. On the other MONS 097381 I L WftlAJttM. vol. 19, no. 7] EFFECTS OK CHLORINATED HYDROCARBONS 307 hand, from Dr. Drinker's work ono would judge that the straight chlorinated naph thalene was nearly as toxic at least as the mixture of it with a small amount of chlo rinated diphenyl. In the condenser factory where we had our eases there is no chlorinated diphenyl used and no acne of the type described in the reports on the insulated wire factories. Da. H. Emmett Kbu.y (Monsanto Chem ical Co., St. Louis, Mo ): 1 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 r have been manufactur ing this chloiinsted diphenyl. It has been our observation that although on one occa sion we did have a more or less extensive scries of skin eruptions which we were never able to attribute as to cause, whether it was impurity in the bcnscnc wc were using or to the chlorinated diphenyl, we have never had any systemic reactions nt all in our men. We have examined them very closely both from what laboratory tests wc thought might help us and from the clinical view point. Alio firm chlorinated diphenyl alone there have hern no eases of systemic poisoning reported. I don't believe that wc can transpose the laboratory results into the actual humans without paying considerable attention to ths volatility of different substances and the way they are being used. Dn. JonN A. Hookey (Consulting Der matologist, Halow-ax Corporation, Detroit, Mich.): I have had roneiderablc experience with the dermatological angle of this prob lem. The experience at the Haiowax plant at Wyandotte definitely was that the derma tosis did increase when compounds were used rsther than the straight chlorinated naphthalenes. From the discussion we have beard today I think the observation Dr. Drinker made that ths rhanees are that dermatological problems will disappear along with the other Is probably true. However, 1 think that certain precautions, certain insurance meaturea, you might say, should be taken in hiring men who are going to work with these products, even though we are going to attempt to get the concentration* low. We saw this morning that the effect of these products was on the liver and that if sonto owe working in these products developed liver damage from some other sourro 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 he 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 dorn have an effect on the liver. If there is any history of syphilis I don't think that tlml msn should be hired. A Kahn test should be taken and I think that it w ould be a good plan to tako Kahn tests on men at stated intervale, because they might develop syphilis after they arc hired. I think (hose things should be done even though wc feel that if the ronrenttation of these vapors in the sir is ki-pt ns low us whs recommended this morning, tire rhanees of having toxic effects arc very Email. Mr. F. U. Kxiuer. I would like loclnnfy a point of J>r. Hookey's. Vou mentioned at the beginning of your talk that your experience in acne condition was more pronounced from the compounds of various materials with cliloronuphthaleue than with the straight chlorr.naphthalencs. Did you mean by that, that the acne condi tion aetunlly was more pronounced with the compounds than with the straight chlorunaphthalene or was that due to the fact that you were in a plant operated in a different fashioo? In other words, you handled your numerous wire comjiound* in more of n batch operation. That is my understand ing from Mr. Drown. Is it a fact that the straight chlorouaphthstenes are less harmful iu so far as sene is eoneerned or is it because of the handling of batch compounds? Dr. John A. Hookey: That is a question that would be difficult to answer. I baaed my statement on the fact that in taking a general survey of these eases after I started working with them the men iu the plant said HONS 097382 308 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY (Scpi. I8S7 that (Key developed acnc more often end more severely after they started making compounds. It may he that it was in the method of the handling. Mm. F. R. Kaimcr: You say that the con dition ine.reaaes with (he increased chlorine content mid we are attributing the acne pri marily to the chlorine radical. If that is true, what are we to associate insofar as these vnrirvua other constituent* are con cerned, such se various plasticizing agents? How much do we know' about those insofar as development of acne is concerned? Some of these compounds have a half dozen con stituents In them other than rhlorodiphcnyl and ehloronephthefrne. We are at the present time considering the chjoronaphthelone an the basic element responsible for the arnc condition which we have. We know very little about w hat the other mate rials may or may not do. Dn. John A. Hookey: I don't know about these other materials. Perhaps Dr. Schwartz would know something more about them. Dit. Lons Schwartz: H is well known In industry that there arc many compounds that cause acne. For Instance, paraffin senes and oil acncs have been known for a long time. Paraffin action, wax senes, are imply a mechanical plugging of the fol licles of the shin by the minute particles of wax that fall on the skin. I think that the acne caused by these chlorinated naph thalene* and diphenyls, because it ia caused by froth---1 was down at the 8wan Chemical Company where they make chlorinated di phenyls and they have acne there just the same as over at Wyandotte where they make the chlorinated naphthalenes--I believe that that la caueed by the same thing, a blocking up of the follicles of the akin, the formation of the comcdone and then the eomedone becomes infected and forms a pustule. They don't all pustulate because they don't all become infeeted. Many of these men never have any pustules. They Just have little whits elevations on their kin. In those people who are ia the acne age, the youngsters of 18, 30, 33 and 28, acne vulgaris is most apt to occur. The sebaeeous gland* arc most active end i hey seem to have it much more than the older people in whom the sebaceous glands are not so active. We keep a dipping of all Articles relating to industrial dermatitis in ni.v office and 1 recently read an article in a German maga zine in which they report in Germany a similar acne condition from chlorinated phenols and chlorinated benzenes and solid waxes, it seems that this acnc-like condi tion is not peculiar to halowax or chlorin ated naphthalenes or diphenyls but can occur with eny condition that blocks up the sebaceous follicles of the skin. Dr. Koyai, Meeker (Special Agent, 8tale ol Connecticut Department of Labor, Hartford, Conn.): 1 am full of question*. As a statistician I am a little bit suspicious of averages, so I should think (hat w e should take maxims as well as averages in getting at the threshold dose or the dangerous im pregnation of the stmonphero with these poisonous compounds. I just wanted to drop that aa a hint for this committee to consider in its work. in spite of wbnt you said at luncheon, Dr. Drinker, 1 still think it is rather impor tant to determine how the plugging of the pores actually docs occur, whether they arc plugged as Dr. Schwartz has suggested, from the particles falling on the outside of the akin or whether they arc plugged, as so many doctors have informed me, from in*i<le as It were. The fumes arc breathed, the substance gets into the blood stream. It is thrown off through the pores of the akin and the pores are plugged. 1 think it is rather important to determine that because it seems to me, from the alight 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 cither 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 coses of very savers dermatitis and 1 am not so sure but what there was some question of liver dam age there. Nobody has said anything about them at all. There is no question than HONS 097383 1 '*p|i vol 19, no. 7} EFFECTS OF CHLORINATED HYDROCARBONS 300 that the condition, whatever the complica tion* might have boon, ram* from handling cold wire, in a confined lira of course. I think till* fired* a great dost more study, Dr. Drinker, (linn you and your associates have been able to g/v* it yet. All I am eurioue about is the way we can administer the protective labor laws in order to protect both tho employer and the employee. I listened with very great interest to the expositions ol suggested pots for the appli cation of hstowax, chlorinated naphthalene and diphenyl. It seemed to me that they left very much to bo desired. 1 don't tee why the application of the halowax com pound, if it is necessary, aa I aaaume it ia, to use this rather dangerous substance, can't be done in a practically closed pot. If you please, Dr. Drinker, 1 with you would ask Mr. Reeves of the Rockbcstos Products Corporation to tell how they have handled ft. If 2 am any judge of equipment and safely devirrs 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 soeme to be entirely adequate. wax we had a head start as far as the ventilating eystcin was concernod, sines cure was already installed and adaptable to s compound with a bt-necne solvent rather than a melted halownx compound. In order to keep the fumes of s highly volatile sol vent under control we did develop n prac tically complete enclosure for the container in which the comftound was placed and exhausted that contuiucr In order to prevent any eacape of the fumes from it. When we changed to the halowax compounds ne fol lowed the same scheme of applying the compounds and used a completely enclosed pot. There is a hole tn one side (or the wire to go in and one on the other sido for the wire to coma out. There is enough exhaust suction pn the enclosure to prevent any fumes from getting out of the openings where the wire enters and leaves. Of course periodically It is necessary to open the pot to replenish the compound or make adjust ments. In that case we have the ventilat ing system interlocked with the door that the operator opens so that when he ofrens it he increases the amount of air travel about ten-fold. Dr. Royal Meeker: What is the veloc ity when the door is open? Mr. U. II Reeves (Vice-president and Genera) Manager, Rockbestos Products Corporation, New-Haven, Conn.)? I will be very glad to tell of our experience If It will help the picture aioug. Our experience has been more or lone parallel with Mr. Kaimer'a In as much as we manufacture the same type of wire. We have avoided the serious pic ture that he ran into, probably due to the faet that shortly after 1933 we were using bcniene ss a solvent for asphaltic materials. We got into anemia difficulties with bon- sene fumes snd hsd to Install a complete ventilating system to remove all those fumes from the machines that spplisd the compounds to the wire. Following the Installation of that equipment we were able to get a substitute for bensene, so we got it out of the picture. ' We are still in the same fix as every one else la as far as finding a substitute for halo wax. Thero is nous that we know of. Con sequently when we went to the use of halo Mn. B. H. Reeves: With the door wi<i open, at breathing level the velocity is 200 feet. That is the linear velocity. We cheek that every week on every opening at very machine with a velometer, a email 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 snd cleaned, because there will be condensation inside the pipe to cut down the air flow and reduce the ventilation efficiency. Dn. Rotal Meeker: What do you think of that trap device shown? Mr. B. H. Reeves: I don't know what to think of that. I don't know whether it would b praetical or not. I was going to ask Dr. Drinker whether in passing the air laden with halowax fumes through the boxes of rata there was any deposit ol halowax in the enclosure. 310 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY {Soft. ifS7 Dn. Cmii K. Drikrem: Vc, I la detectable readily through the outflow pipe. Me. B. I!. Rbbvis: Those in the far end probably didn't get the concentration. Dr. Cecil K. Drinseu: We change the position of the boxes each day. The one* furthest t ty move into the noartit poiilion, ao that over a period of weeks all are exposed equally. complaints wore bona fide. We bod 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 beat in tunnels, ships and so forth, they actually did develop trouble. We have used, of course, the icterus index In following some carbon tetrachloride rases and I wondered what you have to say about that. Is that of no value at all in the case of liver damage in this material? Dr. Fmert H. Bathurst (Consultant In Industrial Hygiene, State Department of Health, Columbus, Ohio): I would like to ssk 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 (he surface of the exhaust pipes in order to rtmeenIrate the deposit in one place and moke it unnecessary to remove long lengths of the ventilating system. While we have found a alight 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 hy cooling the surfaces of the trip. It might be possible, by building a labyrinth id refrigerating coils, to collect it. But then you would have the problem of remov ing it from the coils tiler you had eolloeted it sod it would involve rather complicated procedure. - * Dm. U. L. VoanoacH (Medical Director, General Electric Company, 8chencetady, New York): Wc 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 haa flaws and the fleas have fleae, we also have customers who use wires and cables in tunnels, in endowed spaces, splic ing them together end doing all sorts of tilings. I am not at all certain that era know what the concentration of these chlorinated hydrocarbons is under thooa conditions. About the time we were having eo much trouble at our York factory some of our customer! began oomplaining. We thought we were having a hysteria of halowax mania throughout the country. Some of their Dn. Cacti. K. Drinker: I don't think so until it gets so extreme that we know it any way. Dr. B. L. Vordurom: I did write down r few questions that came to mind. Some of them have been anewered and some arc foolish but I shall ask them anyhow. It occurred to me that if trichlornaphthalcne 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 nftur it has been pretty well damaged. I talked to you and you said you hadn't worked that out with the animals as yet. Dn. Cecil K. Drikkcr: In that ease we set aside a ceriniu number of animals to recover, after knowing that a certain amount of damage had been done. Then we started to kill them but wc invariably ran out of rate before they ran out of lesions. We don't know how long it lasts. Dn. B. L. Vonvnon: Have you given them calcium and glucose sr you would with carbon tetrachloride? Dn. 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, Tbe whole question of calcium in the diet, of giving milk daily to these people may bs worth whilo. I tot. I* Dn quest! what. bility rhlori Mr simph from the tr 1 tbit to obj the to The a indua chlnri Th which our p will I Drink dema comp some we e reirtrv uent and * a iovi able t one o As with IhetH some cfimrt quest the v whet! to Ice !>! ome the n Di more on e> all y MOMS 097385 twf. 19, no. 71 EFFECTS OP CHLORINATED HYDROCARBONS 311 Dr. B. L. Vobboroii: I just bad those questions in mind. I would like to hear what Mr- Brown would say as to the possi bility of using only this one innocuous chlorinated naphthalene. Mr. Sandforu Brown: That would simplify our problem exceedingly, not only from the commercial standpoint but from the toxicity standpoint. But if we did so I think that Mr. Ksiiner would be the first to object because he wouldn't be able to get the technical effects he desires in the cable. Tbe same thing applies throughout all the industry where we arc using these higher ohlorinat''d products. The problem es wc see it, and it it 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 lo try to find a line of demnrrftljon and whether or not within this complicated chemical structure there is some one thing that causes the trouble. If we could take hexaehlornaphlhalcne and ramove 1 per cent of some unknown constit uent with which we are not now familiar and eliminate the toxicity, that would ba a lovely solution. Whether we will ever be able to attain that I don't know. That is one of the things we have in mind. As I said bofore, (hat is one of the things with which all manufacturers of these syn thetic organic products are confronted si some stage, either in their laboratories or in commercial developments. It is largely a question of timing as to when you should do the work, how much you should do, and whether you know how lo do it. You have to learn that first. Dr. Cecil K. Drinker: Unless there ia some other important matter I wifi declare the meeting adjourned. Dr. R. R. Sayers: May I say a word more with regard to what Dr. Hookey stated on syphilis? If you are going to eliminate all your workers who happen to develop syphilis during the time they are working for you, you arc probably goirg to lose some very important employees. It would seem that it would be worth while to rive serious consideration lo seeing that conditions are proper and suitable for them to continue workiug for you and (hat 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. Wo have not found that to be true in other placet and I question whether this is one of (he places. 1 may he in error. Mr. Rakoforr Brown: I aunt 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. 1 believe you ' have all formed (lie opinion, based on what you have heard this morning, that our whole motive here is to conduct (his on n eihieal, scientific and constructive basis. In coliuborntion with the Monsanto Chemical Company wc have a much more comprehensive program in view to carry on. Therefore wc want to continue that seme typo of cooperation. There is one thing that I want tn bring up in that connection, which will have to be observed by the state authorities, w hen they go out to make these inspections. Tlmt is the necessity of not creating mob hysteria on the part of the workmen in the plants where these inspections arc made. Mr. llemperly has run into some very interest ing situations in the various examinations he has made. I know that he would he 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 w here we will be unable to get the full cobpcratiou 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 w ill continue for years. \ HONS 097336