Toxicology of Industrial Chemicals - Advances in Chemistry (ACS

Toxicology of Industrial Chemicals R. E. M A I Z E L L and R. C. PARSIL

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Olin Mathieson Chemical Corp., Niagara Falls and New York, Ν. Y.

Important books, journals, and other sources of information on industrial toxicology are discussed, as well as test methods commonly reported in the literature, standards for expressing de gree of toxicity, and some factors to be considered in evalua tion of test results. The subject is approached from the point of view of the literature chemist rather than of the professional toxicologist, who usually makes the final decision on the test methods to be used in each particular case. Extensive labora tory experimentation is necessary to verify and supplement any available literature.

The earlier writers i n industrial toxicology were concerned w i t h highly volatile sub stances such as solvents, w i t h heavy metals such as lead, and w i t h obviously poison ous gases. The books by Henderson (17), Lehmann and F l u r y (19), and Hamilton (15) are examples. W i t h the development of insecticides, food additives, and related applications of industrial chemicals, interest i n toxicology has greatly increased. It has also come to be recognized that the toxicology of many chemicals may be of a more insidious nature than previously suspected. The field has become complex and now calls on the services of such specialists as physicians, biochemists, biologists, statisticians, and toxicologists. A complete test program for a single chemical may cost $20,000 or even more. Use of the currently available literature can save considerable time and effort i n the planning, design, and interpretation of tests. Current Journals

Industrial and Engineering Chemistry has a regular column on toxicology by H . H . Schrenk of the Industrial Hygiene Foundation at Pittsburgh. The Industrial Hygiene Digest, published by the Industrial Hygiene Foundation, is a n excellent ab stracting j o u r n a l which covers the entire field. The ΑΜΑ Archives of Industrial Health contains original research as well as abstracts from other journals. The Current List of Medical Literature published by the A r m e d Forces Medical L i b r a r y and Chemical Abstracts are other sources of information on current j o u r n a l articles. Other journals of interest include: Archives of Dermatology and Syphilology, Industrial Medicine and Surgery, Journal of the American Medical Association, Journal of the American Pharmaceutical Association, Journal of Pharmacology and Experimental Therapeutics, Journal of Tropical Medicine, Pharmacological Reviews, and Summary Tables of Biological Tests. F o r literature searches going back into the early literature, the literature chem ist can use standard sources such as Chemical Abstracts, Quarterly Cumulative Index Medicus, Current List of Medical Literature, and the Index-Catalogue of the Surgeon General's Library. The U . S. Public Health Service has just issued a valu able index of selected toxicological literature for 1909 to 1953 (26). Books

Π

Hll

In certain fields, there is a quantity of toxicological book literature. A s would be expected, the literature on the toxicity of solvents is extensive. A recent book by B r o w n i n g (6) provides an excellent summary covering also many chemicals not thought of p r i m a r i l y as solvents. 156

A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

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Toxicity literature on pesticides is also extensive. F o r guides to, and sum maries of, available information the following books are p a r t i c u l a r l y recommended: B r o w n (5); "Official Publication," Association of Economic Poisons Control Offi cials (2); Barnes (3); and M a r t i n (21). Sollmann (24) although he deals mainly w i t h pharmaceuticals, has numerous references to the toxicology of chemicals which are also used i n industry. V o n Oettingen's recent book (27) presents a discussion of medical techniques f o r the management of industrial and other kinds of poisoning. This is information not easily located i n other sources. Hamilton and H a r d y (16) have written an excellent up-to-date book on the toxicology of heavy metals and other substances which have long been of toxicological interest. Other recent authors of books of a more general nature include E l k i n s (12) , S a x (23), F a i r h a l l (13), Patty (22), and Jacobs (18).


f

Other Sources of Information

D a t a sheets on the toxicology and safe handling of individual chemicals are pub lished by the N a t i o n a l Safety Council, American Petroleum Institute, and the M a n u facturing Chemists' Association. A recent publication of the state of C a l i f o r n i a (7) is the best summary of a v a i l able information on the toxic effects of chemicals on fish and other water life. Tests with aquatic life are, of course, not ordinarily related to the probable effects on humans. Numerous toxicity studies have been conducted w i t h chemicals used by the A r m e d Services, such as rocket propellants. M u c h of this research is summarized i n reports issued from the A r m y Chemical Center and is frequently made available to the general public. Toxicity information as i t relates to shipping is presented i n the regulations of the Interstate Commerce Commission (8). The " A i r Pollution Abatement M a n u a l " issued by the M a n u f a c t u r i n g Chemists' Association offers the most reliable information on this aspect of toxicology. F o r any specific chemical, the trade catalog of the manufacturer w i l l usually contain some toxicity information. In the event that the information desired is not i n the published literature, the literature chemist has access to such specialized sources of information as the M a n u facturing Chemists' Association, the U . S. Public H e a l t h Service, the N a t i o n a l Safety Council, the Industrial Hygiene Foundation, and the Chemical-Biological Co ordination Center of the N a t i o n a l Research Council. M a n y trade and professional associations have toxicity committees which can supply additional information. The prediction of the probable toxicity of a chemical by reference to the known toxicity of a compound of similar structure is a complex and r i s k y business best left to specialists i n this aspect of toxicity. Toxicity can v a r y more unpredictably and more sharply than physical properties even i n a closely related series of compounds. However, some general guides w i l l be found i n the introduction to F a i r h a l P s book (13) and i n Patty's book (22). Toxicity Test Methods Commonly Used in the Literature

In order to interpret properly toxicity data reported i n the literature, i t is necessary to understand the fundamentals of the various test methods. Some of the most important methods are described here as they are commonly used i n the l i t e r a ture. The comments here are mere description and not recommendations to practice. The actual choice of the test method to be used i n any particular case should be made by a professional toxicologist. Tests are described as acute, subacute, or chronic depending on the nature and duration of the test. Test methods include oral ingestion, inhalation, skin penetra tion, skin i r r i t a t i o n , sensitization, and intravenous and intraperitoneal injec tion. While a l l test methods may be used, emphasis is usually placed on the test o r tests relevant to the method of manufacture, the intended end use, and the probable routes of entry into the human system. O r a l Administration. Data on toxicity by oral administration are most fre quently available i n the literature. This is usually the first phase of testing, which is done to establish the relative toxicity of the chemical. A d m i n i s t r a t i o n may be by stomach tube or by addition to the animal's food and water. N a t u r a l l y , the former A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

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route brings quicker results. Toxicity is designated as LD-o, which means the lethal dose to 50% of the test animals; this is reported in milligrams per kilogram of body weight. The LD^ is a figure chosen a r b i t r a r i l y because it is the median or average figure. When toxicities were originally reported, the "toxic point" was chosen to be the dosage at which no animals died (LD ). This was later changed to the dosage which killed a l l the animals (LD o). To arrive at a figure w i t h a minimum factor of error and a figure that would hold individual variations to a minimum, the LD™ was adopted. The proposal of this standard i n 1927 brought a considerable impetus to research on toxicity The animals most frequently used are rats and mice. Rats are cheap, fertile, healthy, and standardized, but it is much less expensive to use mice ; i n i t i a l cost and the caretaking cost are less. They are, however, more difficult to handle because of their small size. The degree of sensitivity or response to a chemical naturally varies w i t h the animal. A n accurate picture can be obtained by usine; two or three species— for example, the toxicologist may do preliminary work w i t h rats, then dogs, and finally monkeys. The selection of the number and kind of animals to be used requires considerable skill. Typically, the animals selected for testing are young, healthy, and paired for ascertaining sex differences. The material is usually administered to animals which have been without food for 24 hours and it is best given as an aqueous or edible oil solution or suspension. This is not always possible, so alcohol as a solvent is permissible if it does not exceed 2 5 % (15% is preferable). The animals ordinarily have adequate l i v i n g quarters such as individual cages, a i r conditioning, and proper food and water. F i r s t the LD and L D i o o dosages are determined. Next a minimum of four groups of animals con sisting of a minimum of five animals each, and preferably ten, should receive single doses v a r y i n g between the LD and LD^ . More than ten animals in the group does not add significantly to the accuracy of the determination, as most physiological re actions have a 10% deviation in accuracy. A f t e r the animals have received their dosage, they are observed for one week. A n i m a l s that die are examined for gross pathology. The results are tabulated and plotted on semilogarithmic paper, with the per cent mortality on the abscissa and the dosage in milligrams per kilogram of body weight on the ordinate (logarithmic scale so that a relatively straight line is ob tained). The dose k i l l i n g 50% of the animals is the LD of the compound. The National Safety Council uses the following table as a guide in extrapolating animal data to humans (9). 0


10

0

0

Q

m

Dosage R a n g e of LD (Corrected by safety factor)

Rating Dangerously t o x i c Seriously t o x i c H i g h l y toxic Moderately t o x i c S l i g h t l y toxic E x t r e m e l y l o w acute

70

toxicity

1 m g . or less/kg. 1 to 50 m g . / k g . 50 to 500 m g . / k g . 0.5 to 5 g./kg. 5 to 15 g./kg. 15 g. a n d u p w a r d

D

Probable L e t h a l f 7 0 - K g . Man

o s e

o r

A taste A teaspoonful or 4 m l . A n ounce, 28 g r a m s A pint A quart More than a quart

"Range finding" LD , while less accurate than the method described above, is helpful i n estimating the relative toxicity of a chemical. Groups of five rats receive three or four dosage levels i n a series differing by a factor of two. The range find i n g LDw is then calculated. The comparative reliability of the approximate lethal dose and the method of maximum likelihood are discussed in a paper by Diechmann (10). Inhalation. If the means of poisoning by industrial chemicals is to be consid ered i n importance, toxicity by inhalation would be foremost. This is the easiest and most dangerous type of poisoning. It can be rapid, severe, and acute, whereas oral poisoning is usually slow, mild, and sometimes chronic. Fumes from liquids, and dusts from solids and gases can enter the lungs and be absorbed quickly into the blood stream. Control of contamination of the air is difficult. Dust, fumes, and gas continually escape into the air when chemicals are being manufactured and used. Inhalation toxicity may be i n the form of i r r i t a t i o n , asphyxiation, damage to central and peripheral nerve centers, or destruction of the elements of the blood. M a n y of the common industrial chemicals when present i n the air i n high concen50



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trations w i l l cause one or more symptoms. The majority of the well-known indus t r i a l chemicals have been thoroughly enough investigated to provide adequate safety measures. Threshold l i m i t values have been established for many industrial chem icals by the Committee on Threshold L i m i t s of the United States Public H e a l t h Service. Values established by this committee are designed to protect the health and comfort of the worker. Values that would not necessarily impair the health but do cause discomfort of the worker are sometimes reduced to a figure that w i l l give freedom from i r r i t a t i o n . Foulger i n a recent publication (14) and others caution that threshold limits can be taken only as a very general guide. Such limits are not precise scientific figures, owing to shortcomings of analytical methods and differ ences i n working conditions and individual respiratory rates. In a recent publication of the B u r e a u of Mines (25), the 1953 threshold l i m i t values are given together w i t h the variations adopted by the various states; 1955 values are also now available (1) for some 165 compounds. The threshold l i m i t value is usually expressed as M A C or maximum allowable concentration (for an 8hour working day) i n terms of parts per million. A n n u a l revisions of these values seem to be following a trend to more conservative or lower values as human experi ences increase. The Committee on Threshold L i m i t s bases its values on data accumulated from animal inhalation toxicity studies and industrial experience. A safety factor of 10 is used to allow for differences i n response between man and animal. When indus t r i a l experience is not available, animal data and the experience of occupational hygienists must be used i n order to ensure protection of the workers. I f data are rela tively scarce, a larger safety factor is used and this can be as high as 100, depending upon the possibility of engineering control and on analytical methods sensitive enough to determine the amount of the chemical present. Toxicity testing on inhalation can follow the minimum standards as outlined by the National Safety Council. S i x rats of Sherman strain, male albino, 90 to 120 grams i n weight, 5 to 6 weeks of age, are used. They are subjected to saturated vapor at room temperature. I f two, three, or four of the six die after 5 minutes, the hazard is serious; i f two, three, or four die after 15, 30, or 60 minutes, the hazard is definite; i f two, three, cr four die after 2 to 4 hours, moderate; and pfter 8 h~urs, slight. Compounds which are more toxic than " s l i g h t " are given additional study. Skin Penetration. Acute skin penetration can be determined accurately by fol lowing the method as outlined by Draize (11), which involves using a sleeve to hold the chemical i n place on the bared skin of groups of rabbits. S k i n Irritation. Skin i r r i t a t i o n studies are done by using extremely sensitive skin on the belly of albino rabbits. A method has also been outlined by Draize (11), Sensitization. Sensitization work is more complicated. The animals, usually guinea pigs, are injected intracutaneously every other day until a total of ten i n jections have been given. Two weeks after the last sensitizing injection another i n jection is given and the animals are observed for reactions. Tests on human sub jects are sometimes done. E y e Irritation. F o r eye i r r i t a t i o n studies the rabbit is used. The chemical, undiluted or diluted i n a harmless vehicle, is introduced into the rabbit's eye. It is examined then and again after 24 hours. Damage is determined and the chem ical is scored. Injection. Intraperitoneal and intravenous administration are important i n d r u g work, but accidental entry by these routes is improbable i n an industrial situ ation. Intraperitoneal studies are valuable i n studying manifestations of toxicity where relatively slow absorption is desirable or permissible. Acute toxicity tests usually are designed to get quick positive or negative re sults as evidenced by death. Subacute tests are 2- to 4-month tests, during which time there is more opportunity to study such factors as metabolism, growth rate, blood, and fertility. Chronic toxicity tests usually extend for 1 to 2 years and are designed to show up unfavorable effects which might not appear i n the shorter tests and are used particularly w i t h proposed food additives. Interpreting Toxicity Test Results

The complexities of the proper extrapolation of toxicity test results to man are well presented by Barnes (4), H e urges that more attention be paid to the subA Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

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acute tests and i n particular to biochemical studies of the effect on metabolism. Other factors and tests are relatively less meaningful. It is impossible to predict the exact reaction i n man from animal data. Never theless, the majority of substances which are toxic to rodents are toxic to man, and vice versa. Furthermore, small animal testing does give indication as to the type of toxic action which the chemical produces. A safety factor of at least 10 is ap plied to animal test results, as man is considered more sensitive to chemicals. F o r chemicals to be used i n foods or where some experimental data are lacking, safety factors up to 100 may be used. In addition to c r i t e r i a developed by the Committee on Threshold L i m i t s of the U . S. Public Health Service and by the N a t i o n a l Safety Council, other criteria for r a t i n g toxicity have been developed by the Interstate Commerce Commission i n Campbell's Tariff (8); by the Underwriter's Laboratories; and i n regulations issued under the Federal Insecticide, Fungicide, and Rodenticide A c t (1U). F a i r h a l l (13), Foulger (1U), and "Guide to Safety i n the Chemical L a b o r a t o r y " (20) give good general discussions on the value and interpretation of toxicity tests. Conclusions

In looking at any article describing data on toxicity, the following are some criteria to be considered. How was the chemical administered? Toxicity of a chemical may vary, de pending on the route of administration and the number and kind of test animals. Was the test for acute or chronic toxicity? V e r y often a chemical may not be toxic on an i n i t i a l dose, but may have accumulative chronic effects when testing is conducted over a long period of time. What solvent was used i n the test? In the case of oral ingestion the use of excessive quantities of a solvent which is itself toxic may affect the final results. Was a pure or commercial product used? The commercial grade of a chemical w i l l often contain impurities which w i l l affect the final result. Toxicity may v a r y from batch to batch. Thus, the use of a pure chemical i n the test does not have the value i t usually has i n physical and chemical testing. The test should be r u n on the product as it w i l l be manufactured or sold i n commerce. What are the other basic properties of the chemical? Its vapor pressure, odor threshold, and solubility may a l l affect the final results. Volatile substances are usually more of a hazard, everything else being equal. A compound w i t h a high odor threshold may give adequate w a r n i n g before the safe l i m i t is passed. Solu b i l i t y i n body water and fats may be so high that absorption through the skin may be p a r t i c u l a r l y dangerous. Acknowledgment

The assistance of R. E . Taylor i n the development of this paper is acknowledged. Literature Cited

(1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12)

A m e r i c a n Conference of Governmental Industrial Hygienists, Arch. Ind. Health, 11, 521-4 (1955). Association of Economic Poisons Control Officials, College P a r k , M d . , "Official Publication," 1954. Barnes, J. M., " T o x i c Hazards of Certain Pesticides Together w i t h a Select Bibliography on the Toxicology of Pesticides i n M a n and A n i m a l s , " W o r l d Health Organization, Geneva, 1953. Barnes, J. M., and Denz, F . Α., Pharmacol. Rev., 4, 191-242 (1954). B r o w n , A . W . Α., "Insect Control by Chemicals," Wiley, New Y o r k , 1951. Browning, E t h e l , " T o x i c i t y of Industrial Organic Solvents," rev. ed., H e r M a j esty's Stationery Office, London, 1953. C a l i f o r n i a W a t e r Pollution Control Board, Sacramento, Calif., " W a t e r Quality C r i t e r i a , " and Supplements, 1953, 1954. Campbell, Η. Α., " T a r i f f No. 9 Publishing Interstate Commerce Commission Regulations for the Transportation of Explosives," New Y o r k , 1954. Chem. Eng. News, 31, 2719 (1953). Diechmann, W . B., and Mergard, E. G., J. Ind. Hyg. Toxicol., 30, 373-8 (1948). Draize, J. H . , and others, J. Pharmacol. & Exptl. Therap., 82, 377-90 (1944). E l k i n s , Η. B., " C h e m i s t r y of Industrial Toxicology," Wiley, New Y o r k , 1950. A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

M A I Z E L L and PARSIL—TOXICOLOGY OF INDUSTRIAL

(13) (14) (15) (16) (17) (18)


(19) (20) (21) (22) (23) (24) (25) (26) (27)

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F a i r h a l l , L . T., " I n d u s t r i a l Toxicology," W i l l i a m s & W i l k i n s , Baltimore, 1949. Foulger, J. B., "Chemical Business Handbook," Perry, J., ed., pp. 17-1 to 1716, M c G r a w - H i l l , N e w Y o r k , 1954. Hamilton, Α., " I n d u s t r i a l Poisons i n the United States," M a c m i l l a n , N e w Y o r k , 1929. Hamilton, Α., and H a r d y , H . , " I n d u s t r i a l Toxicology," Hoeber, N e w Y o r k , 1949. Henderson, Y., and Haggard, H . W., "Noxious Gases," 2nd ed., Reinhold, N e w Y o r k , 1943. Jacobs, M . B., " A n a l y t i c a l Chemistry of Industrial Poisons, Hazards, and Solvents," Interscience, N e w Y o r k , 1949. Lehmann, Κ. B., and F l u r y , F . , "Toxicology and Hygiene of Industrial Sol vents," W i l l i a m s & W i l k i n s , Baltimore, 1943. Manufacturing Chemists' Association, "Guide to Safety i n the Chemical L a b oratory," V a n Nostrand, N e w Y o r k , 1954. M a r t i n , H . , "Guide to the Chemicals Used i n Crop Protection," Department of Agriculture, Ottawa, Canada, 1953. Patty, F . Α., " I n d u s t r i a l Hygiene & Toxicology," Interscience, N e w Y o r k , 1948. Sax, Ν. I., "Handbook of Dangerous M a t e r i a l s , " Reinhold, N e w Y o r k , 1951. Sollmann, T., " M a n u a l of Pharmacology and Its Applications to Therapeutics and Toxicology," Saunders, Philadelphia, 1948. U . S. Bureau of Mines, "Accepted L i m i t Values of Air Pollutants," Inform. Circ. 7682 (1954). U . S. Public Health Service, Washington, " B i b l i o g r a p h y of Occupational H e a l t h . " Bibliography Series No. 4, 1954. V o n Oettingen, W., " P o i s o n i n g — A Guide to Clinical Diagnosis and Treat ment," Hoeber, N e w Y o r k , 1952.

RECEIVED

November

5,

1954.


Toxicology of Industrial Chemicals - Advances in Chemistry (ACS

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