Document 2J7L9ea6Rb5XxboXo5D62RJr

FILE NAME: Exxon (EXX) DATE: 1970 Oct DOC#: EXX046 DOCUMENT DESCRIPTION: Journal Article - Innovations in Occupational Health: Toxicological Evaluation of Industrial Chemicals - Industrial Chemicals '> xicological evaluation of industrial chemicals is increasingly sophistir ed. Relatively simple tests once considered adequate are no longer v ugh today. The situation as well as the role of the occupational / 1th worker in relation to it are discussed. INNOVATIONS IN OCCUPATIONAL HEALTH: TOXICOLOGICAL EVALUATION OF INDUSTRIAL CHEMICALS l .t E. Eckardt, M.D., Ph.D., F.A.P.H.A. T kre used to be a saying that " If you e velop a better mousetrap, the world " beat a path to your door." Today in-. :stry spends billions of dollars in n arch attempting to develop better pi ducts to get the world to beat a path t<> ils market outlets. In the course of this research it has been estimated that Ki.OOO new chemicals are synthesized l ei'ry year. Obviously, not each of these i> a completely new chemical-- some may represent a synthesis of a material previously identified in nature; others may represent modifications in the struc tural formulas of previously known com pounds in an attempt at improvement. Not all of these new chemicals reach the market place. Ehrlich synthesized 606 compounds before he found his first clinically use ful antisyphilitic drug and had reached 909 before he was able to successfully improve 606. What happened to the re maining compounds is not recorded, but tire likelihood is that they were com pletely abandoned. Industrial experience today is not so different from that of Ehrlich. Our company, for instance, synthesized 406 compounds before they found an effective antifungistat for agri cultural use, how known as Captan. There was a time when an individual or a company could develop a new product and put it on the market with out any consideration for its toxic prop erties. However, many years ago certain responsible industries began to look at the toxic properties of their new products, just as they looked at other properties such as melting point, boiling point, viscosity, and flash point. In part this began as a recognition of product liability claims, but also in some com panies, at least, as a recognition of a re sponsibility that the company had to face up to. Today, particularly as this concerns direct or indirect food addi tives, potentially hazardous household products, and pesticides, statutory re quirements for toxicity hazard evalua tion have been spelled out by federal regulations. In our company responsi bility for review of new product toxicity considerations was delegated to our Medical Research Division about 20 years ago-- long before this was re quired by government regulations. Du Pont with its Haskell Laboratories, Dow Chemical with its Division of Biologi cal Research, and Union Carbide with its Carnegie-Mellon Fellowship are all examples of corporations which recog nized this responsibility before there were regulatory requirements. The in creasing number and expanding size of private toxicological testing laboratories indicate that other smaller companies, who might not be able to justify their OCTOBER, 1970 2011 own in-house toxicological testing pro grams, are increasingly aware of these problems and are seeking assistance with them. Chemical Environment Several committees of the U. S. Con gress have held extensive hearings and issued reports, either directly or in directly through groups of experts, on the importance of our chemical environ ment in health and other matters. Occu pational health, therefore, must increas ingly concern itself with potential product toxicity problems and with the impact of the total environment, as well as the occupational environment, on the health of the people. Increasingly, occu pational health personnel are having to devote more and more time to actual or potential health problems occurring be yond the confines of the plant bound aries. Although perhaps not an innova tion, this is one of the more signifi cant changes in occupational health practice. More and more occupational health personnel are being called upon to con sult with and advise management on toxicological problems. Concurrently many innovations are being introduced into toxicological testing programs, so occupational health personnel are not only having to learn a new field but a field that is constantly expanding and changing. When a chemist or chemical engineer announces the synthesis of a new chemi cal, the first step in toxicological evalua tion is usually the determination of an oral LD30. This test is usually, conducted by administering graded doses of the new chemical to groups of five or more rats and observing the resultant mor tality. The actual LD S0 is determined by plotting deaths against dosage on log probability paper. Thus dosage is usually varied by a log factor, and the data plots out in a straight line from which the LD30 may be read. It is important to remember that the LD30 determined in this way is not a hard and fast figure but may have a considerable standard deviation. Further, different laboratorie may come up with different LDr,o's be cause they use different methods, i.ej_ use of different strains of animals,* fasted or fed animals, varying postdosagi observation periods, and so on. A ri cent report1 compared LD3o determinaj tions on a series of compounds in a serii of laboratories and emphasizes thii variability. At best the LDg<> is an in exact figure which provides the toxi cologist with an indication of the de gree of toxicity of the new chemical, i.e. is it highly toxic, moderately toxic, oi essentially nontoxic. It is important t< realize that adequate testing does noi consist solely of counting dead animals! Observations of the behavior of the ani mals by trained observers at appropriate intervals after dosing may give importani clues to toxicological mechanisms. j Sometimes the chemist will have syn thesized so little of his compound that innovations may have to be introduced into the LD30 determination. Mice may have to be substituted for rats, two ani mals per group used instead of five or ten, and the intraperitoneal route sub stituted for the oral. It should always bi remembered in such cases that a mor< adequate LDso determination should be obtained when a sufficient amount the new chemical becomes available. Expanded Toxicity Testing If the new chemical continues to look promising for some application by the company, larger quantities will be made available for expanded toxicity testing. Tests for dermal absorption and skin irri tation are performed. Rabbits are gen erally the species of choice. The ma terial is applied in graded doses to the g clipped intact and abraded skin in such % a way that the animals cannot lick it off and so complicate the experiment by oral intake. The chemical is also tested i for eye irritation by instilling 0.1 cc or a solution of it into rabbit eyes. At 2012 VOL. 60, NO. 10. A.J.P.H- INDUSTRIAL CHEMICALS in this way is not a hard and fast fig. but may have a considerable standiL mi. the eyes are examined for con- lead interferes with delta-aminolevulinic deviation. Further, different laboratorf j,,,,, c iridal, or corneal effects. This acid (dALA) dehydrogenase.3 As a re may come up with different LD50's , \.i tion should be carried out by a sult, delta-aminolevulinic acid accumu cause they use different methods, |j bserver. A preliminary insight lates in the blood from which it is re use of different strains of anir ini. Iation toxicity can be obtained moved by the urine and excreted. Al fasted or fed animals, varying postdo, !,\ -mg three species of animals to though more work needs to be done on observation periods, and so on. A aii iated with test vapor. For each this, measuring the dALA in the urine cent report1 compared LD 50 determif t\ |. #t procedure adequate observa- may be a more sensitive test for lead tions on a series of compounds in a serw :i,. :ods following administration exposure than either blood or urinary of laboratories and emphasizes in illowed to permit observation of lead determinations. In addition, it is a variability. At best the LD50 is an . li. riocesses, or the production of far simpler test to perform and not so exact figure which provides the toi Iit it damage. Recently, skin and subject to contamination. Where lead cologist with an indication of the i\. ition tests were conducted in a determinations are being made, lead is gree of toxicity of the new chemical, i j l >. i laboratories on several differ- usually being used and there is always is it highly toxic, moderately toxic, |j m pounds.2 The results of these a great danger of contaminating the essentially nontoxic. It is important i n live tests are now being analyzed blood or urine sample with lead. realize that adequate testing does m .ni 1 be published when the analysis If warranted, complex metabolic consist solely of counting dead animali i- . iete. studies may be carried out. In these, Observations of the behavior of the am, mid be remembered that the test- all urine, feces, and expired air are mals by trained observers at approprian iu, us far performed will give in collected and analyzed for the chemical intervals after dosing may give import fun ion only on the acute toxicity of or its metabolites. Frequently radio clues to toxicological mechanisms. . tlii' mical but will tell nothing of the isotope techniques are employed which Sometimes the chemist will have sy I'ui al for cumulative toxicity. From offer a degree of sensitivity that may thesized so little of his compound th tlih nint on, toxicity testing has to be not be achieved with standard analytical innovations may have to be introduce! Hally designed for the chemical techniques. Metabolic studies have into the LD50 determination. Mice may mu : consideration, depending upon its shown that a metabolite of benzene, have to be substituted for rats, two >iit Hied end-use and what was learned namely phenol, is excreted in the urine ; mals per group used instead of five 0| fi'uii. the preceding tests. Thus 90-day therefore, it has been proposed4 that ten, and the intraperitoneal route sti fi cuing studies usually done in rats may urinary phenol excretion be used as a stituted for the oral. It should always l"` ' ade. Two-year or lifetime feeding measure of benzene exposure. The de remembered in such cases that a mol adequate LDgo determination should ' '|i"riments usually using rats and dogs nay be indicated. More recently velopment of the gas chromatograph has made urinary phenol determinations obtained when a sufficient amount o| primates are increasingly used as the accurate and quite specific. jii the new chemical becomes available. 'i`<'imd species in this type of test. At If use of the new chemical is apt to ft die conclusion of either of these tests, involve frequent skin contact, the po Expanded Toxicity Testing sacrifice of the surviving animals and tential for cumulative toxicity by the u If the new chemical continues to look aiclul study of gross and microscopic dermal route must be determined. This promising for some application by fhej pathology of as many as 24 tissues are can be done conveniently in rabbits by company, larger quantities will be made i-nally carried out. During the actual repeated skin applications. This may or available for expanded toxicity testing. testing, studies may be done periodically may not be followed by a challenge dose Tests for dermal absorption and skin irri "f blood counts, urinalyses, and certain to test the possibility that the compound tation are performed. Rabbits are gen nzyme systems in the animals. Thus may be a skin sensitizer. Often, how erally the species of choice. The ma cholinesterase, SGOT, liver microsomal ever, the guinea pig is used as the ani terial is applied in graded doses to the ``nzyme systems, and other enzymes or mal of choice to test the skin sensitizing clipped intact and abraded skin in such J | 1'ody constituents may be studied. Also, properties of a new chemical. a way that the animals cannot lick it j 'f an analytical method exists for the Depending on anticipated use of the off and so complicate the experiment by "* c h e m ic a l, measurements in b lo o d a n d chemical, carcinogenesis testing may be oral intake. The chemical is also tested i other body tissues may be carried out. indicated and undertaken. The procedure for eye irritation by instilling 0.1 cc ^ Recently, as a result of the study of has to be designed on the basis of the or a solution of it into rabbit eyes. At such enzyme systems, it was found that suspected site of carcinogenesis. Thus VOL. 60. NO. 10. A.J.P.H. OCTOBER. 1970 2013 materials suspected of containing poly nuclear aromatic hydrocarbons are usually tested by painting the shaved skin of groups of mice. This may be done two to three times weekly; inbred strains are frequently used. Amino-azo and nitrosamine compounds which may lead to liver cancer formation are more ap propriately tested by feeding studies in rats and mice. Some amino com pounds may lead to bladder cancer. Such tests usually use the dog since rats and mice may not metabolize the com pound to a carcinogen. Recently, pul monary cancers have been produced by suspending a PNA on hematite which is then injected intratracheally as a sus pension into the Golden Syrian hamster.5 Thus it can be seen that there is no " Standard Carcinogenic Test." Testing for carcinogenesis will have to be done in an intelligent fashion based upon one's index of suspicion of carcinogenic action. Other tests that may be indicated in special situations are teratogenic or re production tests. The demand for tera togenic tests arose as a result of the thalidomide episode. The rabbit is usually used in this test and the com pound administered within a specified period during pregnancy. Obviously the pregnant females are sacrificed near term and the fetuses examined carefully for teratogenic effects. In the reproduc tion studies, rats may be carried through three generations, measuring the number of pregnancies, the number of live off spring, the ability of the mother to nurse and wean the litter, and the number of deaths among the litters-- all this while the compound is being administered. A variation of this test may be to measure the egg production and fertility of the eggs in chickens to which the material is being administered. Cosmetic Testing When the chemical is intended for use on human skin, as for instance in a cosmetic, testing may actually even be carried to the human being. Thus, material may be patch-tested in hi beings and, by subsequently apply! challenge, patch-tested for its abilil cause skin sensitization. By using of human beings known to have a tization to a particular compound, possibility of cross-sensitization tested; finally, actual use tests ma; conducted with human beings A few years ago our company veloped a compound which would women's lips stay moist-appearing, wj added to lipsticks. We tested this pound in a double blind experimenj a group of women who were given eil the lipstick with the new chemical or a control lipstick without it. Tfo perimenter himself did not know wl was which. The women were told tq the lipstick for two weeks, then to it in for the other one. They were! asked to compare the two lipsticks to include any irritation they e: enced. Not only did this give us a to evaluate consumer reaction to am ceptance of the new compound in the stick, but also to see if the new pound would cause any lip in i This use test was quite valuable we had received some reports that compound might cause a blisterini the lips. Detergent manufacturers usually ask a panel of women (for af^ to put their hands-- for several houi into a 5 per cent solution of a new tergent before they put it on the marl Also other panels will actually use it report any skin irritation they ol Subacute (90-day) or chronic (I year or lifetime) inhalation toxicity may also be undertaken. These tests complicated and difficult to perform # must be accompanied by engine and analytical support to assure accui determination and control of exposuff atmospheres. Usually multiple specW. are used and may include rats, rabbi#* guinea pigs, dogs, or monkeys. cently the donkey has been reco mended as an experimental animal * 2014 VOL. 60. NO. 10. INDUSTRIAL CHEMICALS the human being. Thi lay be patch-tested in lain pes of inhalation studies.6 Summary and Conclusions l, by subsequently apply patch-tested for its abi sensitization. By using beings known to have a' a particular compoum of cross-sensitization ally, actual use tests with human beings.years ago our compan; compound which would, ! ps stay moist-appearing, ipsticks. We tested this' i double blind experimi women who were given; : with the new chemical] | >1 lipstick without it. If v pollution is a concern, shrimp The toxicological evaluation of indus ,1 c n fish species may be used, trial chemicals is becoming an increas re oncentrations may have to be ingly sophisticated exercise. Whereas iir because these species may ex once it may have been considered suffi bit xquisite sensitivity to certain cient to have oral and skin LD50's and mp Also it may be necessary to inhalation LCS0's, today the range and t t: set of the compound on ducks variety of tests are constantly expanding il wildlife, not only from the as innovations are introduced to meet ml; of the ability of the duck growing needs for safety evaluation. The - -u out also for toxic effects. A occupational health worker must under cm covered toxin, aflatoxin, is stand the utility of these as well as the w !. tor toxicity through its ability limitations and shortcomings since, in iiw liver damage in ducks.7 This creasingly, he is asked to advise and (in esent in moldy ground pea- counsel management in the total en i>. a produced by the mold, As- vironmental health field. rciii avus, which can grow on pea himself did not know] |. The women were told t- .. other similar materials after rvr-: . REFERENCES for two weeks, then to] le other one. They wen ompare the two lipsticl any irritation they only did this give us a c Ilii" toxicologists have been deliim iot of study to the effect of iiiii. , on certain higher nervous e.g., effects on certain condinml v iexes, the chronaxie of the optic 1. Weil, C. S., and Wright, G. J . Intra- and Interiaboratory Comparative Evaluation of Single Oral Test. Toxicol. Appl. Pharmacol. 11:378-388 (Sept.), 1967. 2. Scala, R. A., and Weil, C. S. Personal com munication. consumer reaction to f the new compound inti also to see if the new aid cause any lip est was quite valuable rvr- al so on. The significance of ir crvations is not fully under . this time but, increasingly, more , f b experiments are being performed In this country in an attempt to under 3. Haeger, B. Increased Content of a 5-Aminolaevulinic Acid-like Substance in Urine from Workers in Lead Industry. Scandinav. J. Gin. & Lab. Invest. 9:211-212, 1957. 4. Walkley, J. E .; Pagnotto, L. D.; and Elkins, H. B. The Measurement of Phenol in Urine -ceived some reports might cause a blistei detergent manufacturers : a panel of women (for ir hands-- for several ho] er cent solution of a ne1 ; Maud Iho implications of the Russian ' mlinit*. I have not exhausted the list of posMe tests used to evaluate the toxicity * ! 'n,histrial chemicals. Others would in * "'I'' effects on tissue cultures, effects as an Index of Benzene Exposure. Am. Ind. Hyg. Assoc. J. 22:362-367 (Oct.), 1961. 5. Saffiotti, U .; Cefis, F .; and Kolb, L. H. A Method for the Experimental Induction of Bronchogenic Carcinoma. Cancer Res. 28: 104-124 (Jan.), 1968. 6. Spiegelman, J . R.; Hanson, G. D.; Lazarus, ore they put it on the panels will actually use it* skin irritation they of 3 (90-day) or chronic J time) inhalation toxicity,^ t'a |aniecia, and even effects on domes !]' '"'imiercial animals such as cows, , r<0s- sheep, pigs, and others. It seems hat die more we study toxicology the B>nre innovations are introduced. It is A.; Bennett, R. J .; Lippmann, M.; and Albert, R. E. Effect of Acute Sulfur Dioxide Exposure on Bronchial Clearance in the Donkey. Arch. Environ. Health 17:321-326 (Sept.), 1968. 7. Newbeme, P. M.; Wogan, G. N.; Carlton, >e undertaken. These testt^ P"'-'ible that 10 or 20 years from now W. W.; and Kader, M. M. A. Histopatho 1 and difficult to perforin nii-oiio could discuss the same topic logic Lesions in Ducklings Caused by iccompanied by engim Aspergillus flavus Cultures, Culture Ex : - J " ` hately acknowledge the approaches tracts, and Crystalline Aflatoxins. Toxicol. cal support to assure acci are Using today. Appl. Pharmacol. 6:542-556 (Sept.), 1964. ion and control of ex] s. Usually multiple s] id may include rats, rabl is, dogs, or monkeys. \ donkey has been r an experimental animal Ur. Eckardt is Director, Medical Research Division, Esso Research and Engi neering Company (P. 0 . Box 45), Linden, N. J. 07036. Tiffs paper was presented before a Joint Session of the Industrial Medical Association and the Occupational Health Section of the American Public Health Association at the Ninety-Seventh Annual Meeting in Philadelphia, l'a., November 11, 1969. vol. 60, no. io. S tber, i 970 2015