Document 3QGQ2nJazB7GmzQ3jBkB6G1wy

PLAINTIFF'S EXHIBIT AN R I PR I NT Evaluating the Industrial Hazards of New Chemicals It J. OLSON AND V. It ROWE TW Dew Oiiglcuf Co*. Midland, Mldt Ri|rM4 from IIIISTIIAL ul EI8IIEEIIM C1EWST1T VoL 52, fmf 7%K OmmiImt 1960 Cunlilil 1MB h, Mm OwMmI BmMMt PDMM M U.ft. A. 921001 RowVwK'KIO'I.S ' / Safetv Evaluating the Industrial Hazards of New Chemicals In prescribing safe handling procedures for new compounds and old compounds in new uses, sound toxicological information is combined with knowl edge of proposed use conditions by K. J. Obon and V. K. Rowa, Tfto Dow Chomkaf Co., Midland, Mich Chemical materials and chemical formulations are becoming more and more available to the consuming public and are playing an important role in our industrial and domestic lives. When misused, many chemi cals are hazardous because they are capable of producing deleterious and sometimes serious physiological effects--they are toxic. Toxicity It is of particular importance to realize that toxicity is a property of matter. It is a physiological prop erty which defines the capacity of a chemical to do harm or produce injury to a living organism by other than mechanical means. Chemical and physical properties are estab lished by well known laboratory methods. Likewise, toxicological properties may be defined by con ducting animal experiments in the laooratory. Toxicity entails a defi nite dimension, that of quantity or amount. On this basis, then, any chemical is more or less toxic, dependent upon amount. In a broader sense, everything is toxic. How much is toxic? Too much! Consider oxygen, a natural constit uent of the air we breathe. We inhale enormous amounts of oxy gen. It is essential for life. Is it toxic? It is, specifically so. Too much oxygen administered to the premature iniant is capable of ren dering him blind, a specific physio logical reaction. How about arsenic? When we think of arsenic we think of poison. Very small amouhts are capable of producing serious systemic injury. On the other hand, ai.,*nic, in therapeutic doses, is beneficial. It is used medicinally in treating several diseases. Toxicity is a property and possesses quantitive aspects. Everyone has some concept of poison. We think of red warning labels, the skull and crossbones, and other devices designed to indicate that a material is harmful. A poison may be considered as a sub stance possessing a certain high degree of toxicity. Toxicology is the science that treats of poisonous or toxic sub stances. We handle such materials in our industrial and domestic lives. We experiment with them. We produce them in large quantities. We package them, transport them, and sell them. In many cases, recommend them to the consuming public for specific uses. We may even eat them. Why then are we not in trouble on many counts? The answer is simply, because we do not get too much. It is the job of the industrial toxicologist to define what too much is, and to pre scribe limitations of use so that normal, recommended use does not result in too much. From a toxicological viewpoint, we must consider all types of ex posure and the subsequent effects on the living organism. A material is toxic if it renders living cells in capable of performing their normal function. Chemical injury may be local or systemic. Local injury is the result of direct contact with tis sue. The skin may be burned or the eye may be injured to the extent that vision may be impaired. The respiratory tract and lungs may be injured as a result of inhaling toxic vapors, fumes, dusts, or mists. These are all examples of direct chemical contact with tissues, and the toxi cological reactions may be slight or severe. A material cannot produce internal or systemic injury unless it gains entry into the blood stream. In order to gain entry, a material must contact tissue, be absorbed by it, and subsequently be taken into the systemic circulation. Common routes of entry are through the in tact skin, through the gastroin testinal mucosa and through lung tissue. Once in the blood stream, a toxicant may elicit general ef fects, but more than likely the criti cal injury will be localized in specific tissues or organs. DtgrMt of Hazard The extent of the injury produced by a material may depend upon several factors such as physical state, concentration, and duration of ex posure. At this point, we must introduce another basic concept, that of hazard. Hazard treats of the probability or likelihood that a substance will cause harm. In eval uating hazard, toxicity is but one (actor. Others are chemical and physical properties, warning proper ties such as odor and pain, use, and type and number of customers. Two liquid materials may possess the same degree of high toxicity upon acute inhalation of vapors. One material may be odorless, color less, and nonirritating to the eyes and nose. The other may have a pungent or disagreeable odor in minute concentration or be an eye or respiratory irritant. By comparison, the material with the warning prop erties presents a lesser degree of hazard. Its presence can be de tected in time to avert injury. In another case, a material used by technical personnel as a chemical intermediate presents much less of a hazard than if it were offered to (prMari from WOUSTIIAt AND DMMIIISM CMSMIJTtV, Copyright 1960 by fho Amricow Qitoicoi Sodoly and roprintod op ptOTMi i> noiM.'u the consuming public as a cosmetic. The hazard in the latter case is increased on two counts--the prob ability of contact is increased and the customer is unassuming. Evaluating Chemical Materials In evaluating the toxicity of a chemical, the toxicologist has several devices at hand. To start with, there may be records of human ex perience available. This is partic ularly true for older chemicals such as caustic, kerosine, and others. Medical records through the years bear out the harmful .effects of caustic materials if allowed to con tact the eye or if inadvertently swallowed. Less notorious chemicals have found their way into the tech nical literature which > readily available to the enterprising toxi cologist. In the fast moving field of chemistry, however, we are fre quently confronted with evaluating the toxicity of new substances, per haps never having been made or tested before. These materials must be taken into the laboratory and subjected to animal experimentation. In the area of animal testing, the horizons are essentially unlimited. The toxicologist may do quick, limited, range-finding studies or he may conduct long-term chronic exposure experiments. His criteria may involve only a single gross observation or they may require meticulous histological preparation of tissues and subsequent microscopic examination. Pharmacological tech niques may be employed to explore mechanism of action. In some cases, testing may be on human subjects. He begins with an evaluation of the problem. He learns what the material is and how it is to be used. He then devises laboratory experi ments to simulate use-conditions. The importance of problem evalu ation must be emphasized. All factors must be brought into focus and the approach placed in the proper perspective lest we spin our wheels and perhaps jeopardize the health and safety of our employees or detain the development of a new product. The toxicologist so licits the understanding and coopera tion of everyone concerned in this matter. He wishes to know all chemical and physical properties of a material, what stage of develop- 921001 ment it's in, in what form or con centration it is to be used, and how it is to be handled. It is important to define the problem. If it's a legal problem, will it involve FDA, a State Household Poisons Act, or will someone be sued? Perhaps one is simply comparing several compounds of equal efficacy to determine which is the most favor able from a toxicological viewpoint. Certain handling problems may require very limited laboratory in vestigation, to determine effects of direct skin or eye contact. Armed with this information, the toxicologist is ready to conduct laboratory experiments. The data obtained reveal, for example, the 'type and extent of injury which might be expected from direct eye contact with a chemical. Injury might be very slight, or severe, sev ere to the extent of resulting in perma nent impairment of vision. The effect of washing is particularly im portant to note for it indicates how rapidly the material reacts with the eye tissue. It is not uncommon for the toxicologist to encounter a chem ical that is essentially harmless if lei surely washed from the eye, which if allowed to remain, would produce loss of vision. Some chemicals, of course, are capable of exerting ex tensive injury almost immediately upon contact. Such materials are particularly hazardous and for their handling, the toxicologist must pre scribe tight fitting chemical workers goggles whenever the likelihood of eye contact exists. It is necessary to study the effect materials may have when they con tact the skin. Several reactions may occur as a result of chemical contact with the skin. A common reaction is a chemical burn charac terized by necrosis or denaturation which usually is followed by a scab formation and scarring. Many chemicals produce skin irritation of a minor degree. Ef fective organic solvents frequently cause such a response, sometimes referred to as eczema. Some chemicals have the ability to penetrate intact skin. They are absorbed through the skin, into the systemic circulation, and in many cases, very small amounts may rapidly produce serious internal in jury, even death. RowV*K *" ' ^4^ Some chemicals are so-called skin sensitizers. They are capable of producing an allergic, edematous, contact-type dermatitis in humans. Skin may become sensitized as a result of a single massive exposure or to contact with minute amounts of material over a long period of time. Careful interpretation of skin irri tation data, along with the knowl edge of physical and chemical prop erties, permits the toxicologist to evaluate hazard and in turn pre scribe precautionary measures to be observed for safe handling in research, production, or use. The toxicological effects of vapors, gases, fumes, or dusts are deter mined in the laboratory by actually exposing animals in fume chambers. From such studies the toxicologist gains information regarding no-effect levels as well as those levels which produce systemic injury of various types and degrees. It is not unusual to conduct metabolic studies on animals. In some cases, it is advantageous to know what becomes of a chemical during the process of metabolism. The toxicologist can frequently es tablish that a material is rendered f innocuous and efficiently eliminated^ by various excretory mechanisms. The effects of chemicals, when taken by mouth, are observed in the laboratory by feeding graded amounts to animals. The dose which proves lethal to 50% of the animals fed is used as a measure of relative acute toxicity. This amount is known as the LDs*. Chronic feeding studies are con ducted to determine the effect of ingesting small amounts of materials over extended periods of time. This procedure allows the toxicologist to establish no-effect levels as well as levels which elicit toxic signs and symptoms. This information is use ful in evaluating a chemical for use as a food additive, for establishing residue tolerances for agricultural chemicals, and in evaluation of in dustrial hazards. Basically, the toxicologist will as sume that if a given material elicits a specific effect in test animals it is probable that it will do likewise in man. The seriousness of this effect will guide his choice of safety fac tors. In this regard, the experience ^ of the toxicologist is invaluable. VOL SZ NO. 13 DfCSMSSI >MO 79 A Using Toxicological Information As an example of how toxicological information is used, it is of particular interest to follow the thinking of the toxicologist in evaluating the ap propriateness of a solvent material for a rather specific use. The term "bucket solvent" refers to an organic chemical used in small containers for the manual cleaning of metal parts, floors, and all sorts of objects. The containers may be buckets, cans, or small tanks, and the usual quanti ties of the solvent range from several quarts to several gallons. We have probably all used "bucket solvents" in our own homes. This example is chosen because of its obvious universal use, and be cause normal use assumes gross exposure to the liquid and vapors. For such use, the toxicologist would prescribe the ideal solvent--a color less, odorless, nonflammable, nonirritating, nontoxic material posing no handling hazard whatsoever. No such organic chemical exists. It is recognized that many different substances may be used for miscel laneous cleaning purposes. The fac tors of cost, flammability, cleaning performance, and volatility tend to limit the choice to certain aromatic hydrocarbons, benzene, toluene, and xylene, to certain petroleum frac tions such as Stoddard solvent and to the chlorinated aliphatic hydro carbons, carbon tetrachloride, tetrachioroethylene, trichloroethylene, methylene chloride, and 1,1,1-trichloroethane. These solvents are all readily available for use. Let us consider the various haz ards. What about ingestion? All of these solvents would be con sidered to have low acute oral toxicides; that is, their LDw values are in the range of several grains per kilogram of body weight. There should be no problem from ingesdon incidental to the use of solvents. There is litde need to differentiate between common solvents in this regard, although there are signifi cant differences between them. Harmful effects can result only from willful or accidental swallowing. Workmen have been known to drink solvents for the intoxicating effects and children have accidentally swal lowed them. With all organic sol vents, it is readily possible to swallow sufficient amounts to produce serious systemic injury, even death. All should be stored in clearly labeled, appropriate containers, not "coke bottles," and stored out of reach of small children. Workmen should be made to understand that solvents are not substitutes for ethyl alcohol. What about eye irritauon inci dental to use of a "bucket solvent"? Here again, there is probably no real need to differentiate between them. They are all capable of pro ducing local irritation, particularly to the conjunctiva, but prolonged or permanent effects are not likely. Owing to the unique character and importance of the eye, it is desirable to protect against all foreign sub stances. Minimal eye protection or safety glasses, if you wish, should certainly provide ample safety meas ure for most operations. When it comes to skin contact, it is virtually impossible to find a substance which does not have some adverse effects. All of the effective organic solvents extract natural fats and render the skin dry in appear ance and feeling. Repeated ex posure may result in inflammation, scaling, Assuring, and some may even burn. Solvents such as xylene, and orthodichlorobenzene may produce an irritation upon relatively short contact. Some materials, particu larly crude petroleum fractions, may cause acne-form dermatitis. The recommendation for all "bucket solvents" is that measures be taken to avoid prolonged and re peated contact with the skin. It is recognized that short, infrequent contacts may not be harmful. For many solvents, there are gloves and protective garments which are suffi ciently impervious to afford pro tection where excessive contact can not be avoided. A candidate for use as a "bucket solvent" must not have a high toxicity by absorption through the skin. It should be sufficiently low in toxicity that occasional contacts are not harmful, even though they may be extensive and somewhat pro longed. Some of these common ma terials with which we are concerned meet this qualification. The hazard from vapor inhala tion is the most important problem in the use1 of a "bucket' solvent." Consider a bad actor, carbon tetra chloride. "Carbon tet" can be tolerated at a level ranging up to 25 p.p.m. in the atmosphere. One can expect minimal effects from single exposures to 50 to 300 p.p.m. and serious effects from exposures of 1 t hour to 8 hours at concentra tions from 300 to 1000 p.p.m. This latter condition mav well prove fatal and can be anticipated in the use of "carbon tet." Benzene and carbon disulfide generallv fall into this same category. At the other end of the gamut, we find 1,1,1-trichloroethane. It can be tolerated without effect for pro longed and repeated exposure at concentrations up to 500 p.p.m Single exposures having minimal effects range from about 700 to 1000 p.p.m. Serious effects may be expected from exposures of `/i hour to 8 hours at concentration of the order of 5000 p.p.m. Atmos pheric concentrations exceeding 500 p.p.m. would be unlikely in the use of 1,1,1-trichloroethane as a "bucket solvent" where reasonable natural or artificial ventilation is present. In the evaluation of hazards in the examples cited above, it is important to consider the toxicological con sequences of overexposure, as well as the concentration which produces them. "Carbon tet" produces anes thesia and nausea as well as severe liver and kidney injury. 1,1,1-Trichloroethane, on the other hand, produces anesthesia, but is not likely to cause appreciable organic injury. If a workman were to be overcome from the vapors of "carbon tet," he might recover from the anesthesia but likely not from the organic injury. In a parallel case of 1,1,1trichloroethane, about all he would need would be a few minutes in fresh air. His recovery, likely, would be complete and uneventful. The other solvents, except for benzene, which is highly toxic, fall somewhere between carbon tetra chloride and 1,1,1-trichloroethane in suitability for use as a "bucket sol vent." ThrasheM Limit* On the subject of air-borne con taminants, published MACs--maxi mum allowable concentrations--are frequently misunderstood and mis used. Most environmental meas urements are concerned with the amount of material that is being breathed. This is a major industrial problem because one of the easies, 80 A MOUSTHAL AMO BMMBUNO CHMMSTtY 921001 RowVwK 0004-S:. ways to become overexposed to a chemical in a work environment is by inhalation. The acceptable ex posure by inhalation in the case of vapors is usually expressed as parts per million by volume of air and particulate matter, such as mists and dusts, as milligrams per cubic meter. There are several ways of arriving at this value. It may be a result of careful toxicological evaluation with animals; it may represent measure ments actually made in a work en vironment which was known to rep resent acceptable or barely accept able exposures. In still another case, the MAC or Threshold Limit may have been chosen on the basis of similarity in chemical structure with an already established material. Somedmes the figure may have been chosen as one which would be necessary in ord - to avoid real systemic injury or, on the other hand, the control may be aimed at avoid ing unpleasant or painful exposure. In some cases, safety factors are built into the control figure, while in other cases the figure may repre sent the actual concentration which barely avoids injury. There is no standardized procedure or method for arriving at a maximum allow able concentration. If one is to compare toxicity of materials, he must not overlook differences in consequences of overexposure. Suppose that 100 p.p.m. of material "A" represents the control necessary to avoid headache or dizziness whereas the 200 p.p.m. required for control for chemical "B" is designed to avoid serious liver injury. The dangers of com paring the materials on the basis of suggested control figures become obvious. At best, MAC values serve only as guides for controlling en vironmental health hazards. If one always stays below the quoted figure, it is unlikely that injury will occur. Adapted from a talk presented at 48th National Safety Congress, National Safety Council. Chicago, 111., Oct. 17-21, 1960. 0 921001 RowVerKI- 045*1 I- Y Paiirrso m U. 9. A. VOL 32, NO. 12 POTIWH IMO 81 A