Document 15ZpbDoL1mon86VeJ95G0Ewra

FURTHER OBSERVATIONS ON THE POSSIBLE SYSTEMIC TOX ICITY OF CERTAIN* OF THE CHLORINATED HYDROCARBON'S WITH SUGGESTIONS FOR PERMISSIBLE CONCENTRA TIONS IN THE AIR OF WORKROOMS T Cecil K. Drinker Department of Phi/eiolopy, Harrard School of Public Health, Boeton, Matt. Reprinted from The Joi-rxal or Ixdoatmal Htoiexe and Tozicoloct Vol. 21, No. 5, May, 1031) GBRN001992-- LEXOLDMONOOI863 (Ufriattrf frB Tn Jomu or Zatcvmo& Brann n To ToL SI. No. I. Ihy, tM FURTHER OBSERVATIONS ON THE POSSIBLE SYSTEMIC TOX ICITY OF CERTAIN OF THE CHLORINATED HYDROCARBONS WITH SUGGESTIONS FOR PERMISSIBLE CONCENTRA TIONS IN THE AIR OF WORKROOMS* Cxcn. K. Dukkxb Dtfortmtoi of Pkfnolof)/, Henard School of Public HtalDi, Botton, Matt. INCE 1937, seven! papers have Tex Emcr or High arm Low S appeared dealing with the sys temic effects of certain of the Calcium Intaxx ok Animals In haling High Concentrations or a chlorinated hydrocarbons. These areMixture or Penta and Hxxa- listed in the bibliography in the order CHLORNAPHTHALXNX8 (CHLORINE of their appearance (1, 2, 3, 4, 5). 62.6%). The first of these papers included recommendations as to safe concentra tions in the air of workrooms, that is, concentrations that would cause no ill effects to individuals who breathed them throughout a working day. It also mentioned certain other observa tions, such as the effects of diet on toxicity, which were being made at the time but which had not progressed far enough to merit description. It is now passible to report upon these matters and to list a fairly large num ber of chlorinated hydrocarbons to gether with permissible concentrations in air. in*.Bacuivtd for publication February 10, It is well known that a diet rich in calcium is markedly effective in pre venting the acute yellow atrophy of the liver produced by carbon tetra chloride (Lamson et si. (6)). To dis cover whether calcium in the diet would protect against liver damage from a toxic chlorinated hydrocarbon, 30 adult white rats were placed upon a diet of lean horsemeat, starch and lard, a combination adequate for main tenance but very low in calcium. Another group was given a diet con sisting of dog chow, milk, lettuce and eggs, with added calcium lactate,--a ration very high in calcium. Both groups were exposed simultaneously BBRNQO1993 e LEXOLDMONOOI864 168 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [mL i, no. I to inhalation of high concentration* treatment. No difference* wen noted . of a mixture of penta and bexachlor- and one cannot expect any efficacy ' naphthalene* (chlorine 62.6%), an from xanthine either in the prevention average of 11.21 mg. per cu-m. for 16 or treatment of liver disease due to hour* a day. this chlorinated hydrocarbon, and in After 16 day*, 12 high calcium diet all probability the same negative rats were alive and 7 of the low cal result would be encountered in con* i dura group. At intervals animal* nection with allied toxic compounds. i were killed for examination. In both ! group* the liver was abnormal greedy Evidence roa the Destbuctxon or a and microscopically, and in both Mixture or Penta and Hex- i groups animal* died from liver dam* ACHLOBNAPHTHALENES (ChLOBIXZ i age. It was impossible to consider 62.6%) in the Boot. ' ; that the high calcium diet was in It has always been a question as to | the least degree protective. It may, whether the chlorinated hydrocarbons ; therefore, be concluded that adding which have been examined by our : calcium to the diet of workers dther selves and by others do harm per se in the form of extra milk or of calcium or whether toxicity depends on their ; lactate will not prevent liver damage. breakdown in the body with the liberation of something harmful to the Tbs EmccT or Injections or Xax- liver. A partial answer has been ' thiite on Actuals Inhaling High obtained by feeding the above com : Concentrations or a Mixtobx or pound to rats and dogs which were on Penta and Hexachlornafhtha- a low chloride diet with uniform lenes (Chlorine 62.6%). - excretion of chlorides in the urine. In 1937, R. C. Neale (7) published When these animals received the a brief paper in which he claimed that chlorinated hydrocarbon the urinary : rats injected with sodium xanthine chlorides rose. This indicates that : became markedly resistant to carbon the body certainly has power to de ? tetrachloride. This suggested that tach chlorine from this compound, and j xanthine might have similar protective it is probable that the same condition ; power over liver damage from the is true for allied toxic compounds. ' chlorinated hydrocarbons on examine* ; tion in this laboratory. Accordingly The Emcr or Increasing the 38 adult white rats were caused to Sodium Chloride nr the Diet ; inhale a mixture of penta and bexa- upon Animals Recetvino Toxic ehlomaphthalenes (chlorine 62.6%) Doses or a Mixture or Penta in concentrations averaging 15 mg. per AND HeXACHLORNAPBTHALENES 1 eum. for 16 hours daily. One group (Chlorine 62.6%). of 20 rats was given 20 mg. of xanthine On the ground that chlorides might subcutaneously every other day and be fundamentally associated with tox 40 mg. of xanthine by stomach tube icity, a group of 15 rats wss fed a low on the alternate dayB. The second toxic dose of this compound sod com group of 18 rats had the same exposure pared with a similar group on the to the compound without xanthine same dosage plus a "***! increase in I BBRN001994 LEXOLDMONOOI865 |wL ti, me. * xa were noted any efficacy .he prevention liseaae due to arbon, and in sme negative itered in con ic compounds. TRUCTION or A A AND HEXs (Chlorine question as to 1 hydrocarbons mined by ourio harm per te pends on their iody with the ; harmful to the iwer has been Jie above coms which were on with uniform i in the urine. * received the ion the urinary indicates that es power to de i compound, and s same condition ic compounds. NCREAStXO TEE : IN tee Diet ecexving Toxic tore or Penta INAPETHALENEB ). it chlorides might moisted with toxats was fed a low mpound and com ar group on the narked increase in May, list] TOXICITY OF CHLORINATED HYDROCARBONS 157 chloride intake secured by giving 5 ce. per kg. of body weight of 4% sodium ehloride solution duly. No differences were found between the two sebaceous- glands. AO that can be said at the moment is that increased chloride intake does not increase systemic toxicity. TABLE 1 A List or 14 Crlobbcatsd Htsbocaxbons, wits Csmbxxs Conrans am Psainssau Lnom (is ko./cojc.) ros tbs Am nr Workbooks* . -- toHmenn tCalBtUnI % M.#C.k/ 1. Triehlornaphthalent plus a trace of tetraehlornaphthalene. Tasted 49.9 10.0 2. Tetra and pentaehloraaphthalenee. Tested upon rata by inhalation 66.4 1.0 t. Penta and hciachJomaphtheienea. Tested upon rats by inhalation and 62.6 0.5 4. Tetra end penUchlornaphthiienes plus refined ehlorinnted diphenyl. Tested upon rate by feeding.............................................................. 43.6 0.6 i 90% penta and hezaehlornapbthalenes plus 10% chlorinated diphenyl h#nsi*. Tested upon rate Ky ifihfiUtiM tnd Ky fMNiing ............ 68.0 0.5 0. Chlorinated diphenyl plus chlorinated diphenyl beasene. Tested upon rats by inhalation and by feeding........ ......................... ................ 66.0 64.0 67.0 50-55 0.5 0.5 0.5 0.5 10. Hexaehlor diphenyl oxide plus 5% trichlorsaphthalene. Tested upon rate by inhalation.............................................................................. 60-66 11. Henehlornmphtbelene end ends chlorinated diphenyl. Tested upon ffiti Ky tnhftUtiAtb................................ ............................................ Un- 0.5 0.6 known 12. Specie) chlorinated naphthalene. Tested upon rate by inhalation...... 60-56 0.5 13. Chlorinated diphenyl. Tested upon rats by inhalation....................... 68 10.0 11. Chlorinated diphenyl beuene. Tested upon rets by inhalation.......... 60 0.5 * Tbs analytical method aad apparatus used routinely for field determination! it that described by Tebbeas (Tula J., 1$, 204 (1037)) and by Drinker at cl. (ibid., p. 283). groups, and it may be concluded that chlorine increase secured through the diet does not enhance toxicity. This experiment was done in order to find out whether increase in chloride intake during hot weather might be harmful. A particular phase of the problem, the posable enhancement of typical skin lesions by increasing ehloride in take, cannot be decided by experi ments on fur-bearing animals with no Tex Systemic Enron or 14 CHLO RINATED HtOROCA&BONB WITH SUG GESTED Limits tor Concentra tions in the Air or Workrooms. The technic for inhalation and feeding experiments upon rats has been fully described (Drinker et al. (1)). It has been uniform for all the compounds listed in table 1, and for each group of experiments 24 to 48 GBRNOO1995 LEXOLDMONOOI86B 153 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [ief. tl, no. I animals have been sacrificed and toxicity because it is not broken down examined grossly and microscopically b the body, but that would seem so as to gab very complete post the probable explanation. Compound mortem reports. number 12 was prepared especially b The first 0 substances b table 1 order to have a substance for test have been dealt with b previous pub which should fall in chlorination be lished reports (cf. 1 and 3 b bibliog tween compounds 1 and 2. It proved raphy). In connection with them it somewhat toxic and, in addition to was recommended that b the ease of changes b the liver, caused eye ir trichlomaphthalcne and compounds of ritation and b one instance cata . lower chlorination a limit of 10 mg. per racts. The substance is not in com cu.m. be permitted, the idea being mercial use and evidently at the that the essential feature of the action temperatures used for volatilization of these compounds, namely damage gave off some sort of irritant, possibly to the liver, did not become prominent hydrochloric acid. until a chlorine content of 50% was With the exception of this isolated reached. So far as trichlomaphtha- effect upon the eyes, wc have seen no lene is concerned the limit of 10 mg. lesions from any of the 14 compounds should be allowed to stand, since listed except b the liver. The char nothing has occurred which indicates acter of these lesions has been thor the necessity for changbg it. The oughly described by Bennett el al. second compound, a mixture of tetra (3). These additional data and the and pcntachlornaphthalenes is b com tolerances recommended deal spe mon bdustrial use. A tolerance of cifically with systemic effects since one 0.5 mg. per cu.m, was formerly pro can get no information as to chloracne posed for it, but on the basis of laborer b the skb from observations upon tory and field experience it is apparently entirely safe to increase this to 1.0 mg. per cu.m. The sixth compound has been listed previously as chlorinated diphenyl. It contained 65% of chlorine and proved very destructive to the liver. Later experiments with compound 13, fur-bearing animals. But it may be pointed out that where industrial workers have been careful as to clean liness and where air concentrations have been kept within the limits sug gested, skb lesions apparently cease to occur. which contabcd 6S% of chlorine and SmntABY which was also labelled chlorinated diplienyl, were a surprise to us since this second compound was almost non-toxic. On inquiry it was found that substance 6 was b reality a Certain experiments carried out upon large groups of white rats indi cate the followbg: 1. A high calcium diet has no pro mixture of chlorinated diphenyl and tective effect against the characteristic chloriuatcd diphenyl benzene and that liver lesions reused by these com number 13 was actual chlorinated pounds. diplienyl. We have no reformation* 2. Administration of xanthine does as to whether this last compound lacks not prevent liver injury. ' 6BRN001996 LEXOLDMONOOI867 [m<. tl, no. * broken down would seem Compound especially in mce for teet orination be* 2. It proved i addition to aused eye irQgtnnce catas not in com*. ently *t the volatilization itant, possibly >f this isolated : have Been no 14 compounds er. The charhas been thor* Bennett et aL data and the led deal epeeffects since one as to chloracne serrations upon But it may be here industrial eful as to clean concentrations i the limits sugipparently cease RT its carried out ' white rats indi- diet has no prothe characteristic by these eom- o? nntbine does jury. iW) TOXICITY 07 CHLORINATED HYDROCARBONS 159 3. When a mixture of penta and hcxachlornaphthalene is given to dogs by mouth, the urinary chlorides rise, indicating that in some way the body cells detach chlorine from this com pound. 4. A high chlorine intake does not enhance toxicity. 5. A tabulation can now be preaented covering 14 chlorinated hydro carbons with permnrible safe concen trations in the air of workrooms. BIBLIOGRAPHY V 1. Daman, C. K,, Yims, M. 7., am Bskxstt, G. A.: The problem of possi ble systemic offsets from certain chlorinated hydrocarbons. Tms t, ass (1917). 3. Tumm, 7. B., axd Jura, N. .: Liver lemons eanstd by chlorinated naphtha- leas. Am. J. Hyg., S7, 19 (1938). ^ S. BmmTT, G. A., Dunn, C. K., Wamssx, M. 7.: Morphological changes in the livers of rats resulting from exposure to certain chlorinated hydrocarbons. Tms J., SO, 97 (1938). / 4. Cuubt, R V., Mena, I., no Hnca- nros, 0. H.: The metabolism of chlorinated naphthalenes. J. Bid. Cbem., iff, 403 (1939). 5. Gbsexscbo, L., Matbu, M. R., in Burrs, A. R.: The systemic effects re ' suiting from exposure to certain ehlcrinatsd hydrocarbons. Tms J.. it, 39 (1339). 6. Lxusox, 7. D., Mixor, A. 8., urn Robbzxb, B. H.: The prevention and treatment of carbon tetrachloride in torication. J.A.M.A., to, 343 (1929). 7. Kuu, R. C.: The protective action of certain purines igainit liver neeroeii produced by carbon tetrachloride and chloroform. Science, tt, 83 (1937). GBRNOQ1997 LEXOLDMONOOI868