Document 3J5Bj5dq3JqObEMp4VXVBvqE

F B- -- o r--: iJJlLU pJcZ-pg SjuV^ 772. f, ^ | jlso ur I i tllti!) f Inii. I then c | jC'ie f | jlid d: How much benzene causes cancer? The question is controversial. Industry is thus threatened with over-reaction to the substance's potential carcinogenicity. Here's a rundown on benzene's background as a toxic material and where it is leading the refiner John J. Thorpe, Exxon Corp., New York For many companies, compliance with the new U.S. permanent standard for benzene exposure* will be possible but costly. For others, it will pose major problems. But the basic reason for industry's opposition to this standard is not economic. The reason is twofold: 1. Control of benzene exposure to the lowest feasible level because it is a carcinogen is unscientific because it denies the concept of a threshold and a dose-re sponse relationship. To accept this point is to legitimatize the generic standard for carcinogens. 2. The diversion of scarce medical, technical and man agement resources cannot be justified on the basis of the theoretical gains for society as a whole. Courts will decide. The issue is now joined in the courts so die last chapter is still to be written. An optimist might hope that something akin to the scientifically de fensible conclusions of the International Workshop on Benzene held in Paris in November 1976 will emerge, namely: The Workshop discussed but could not agree on whether there was a concentration below which there would be no leukemogenic effect clearly at tributable to benzene. Despite this inability to exclude the possible induction of leukemia at benzene exposures below 10 ppm it was agreed that such a case would be a rare occurrence. Benzene exposure should be controlled to be as low as possible but in no case should the Time Weighted Average exceed 10 ppm for an 8-hour day and a 40-hour week. The average should be based on a single work day. The ceiling value should not exceed 25 ppm based on a 10-15 minute sampling period.1 * U.S. permanent benzene standard (February 1978) 1. A level of 1.0 ppm in air over an 8-hour period 2. A 5 ppm ceiling for any 15-minute period 3. An 0.5 ppm action level for monitoring and medical sur veillance Time and the courts will decide if such optimism is justified. In the meantime, it is well to know as much a< possible about benzene's metabolism, toxic effects, regu latory history in the U.S. and the new standard's contents, as a guideline for the contrcversv's likely outcome. Metabolism. After inhalation of benzene by a mammal . about 40 percent is eliminated unchanged in expired air.The liver converts the remainder to benzene oxide. Subseouently, some of the benzene oxide converts to phenolby spontaneous management. Some goes through benzene glycol formation to catechol and trans-trans muconic acid. A third portion reacts with glutathione to produce phenylmercapturic acid. The phenol undergoes conjugation to form phenylsulfates and phenylglucuronides or goes through hydroquinol to conjugation and elimination. Most catechol is con jugated and eliminated, small amounts being oxidized to hydroxyhydroquinol.2 Acute toxicity. As shown in Table 1, direct skin contact dilates blood vessels, reddens and irritates the skin and removes natural fat. If this sequence is repeated the skin dries, scales and cracks. In general, however, normal skin .does not absorb benzene rapidly. F.ve contact produces similar irritation. If benzene is not removed serious tissue injury occurs. Mucous membranes (nose, mouth, throat, lungs, etc.) TABLE 1--Acute benzene toxicity Skin Vasodilatation Erythema Irritation Drying Eye Itching Ucrimation Irritation Mucusmembrane* & lungs Irritation Vasodilatation Pulmonary edema Hemorrhage Tissue necrosis Exhilaration Drowsiness Fatigue Dizziness Headache Nausea Tachycardia Dyspnea Unconsciousness Convulsions Tremor Death MCD 000001813 TABLE 2--Effects of benzene vapor on man Air concentration p.p.m. mg/I ?n ftQfM9,noo 65-6 L 3,000 1,500 500 150-50 - 25 (MAC)* 9.6 4.8 1.6 0.48-0.16 0.08 Duration of exposure (minutes) _____ 5il0_____ 1 30 30 60 60 300 480 Effects Fatal Dangerous to life Endurable Serious symptoms Symptoms o( ilness Headache, lassitude, weannes* None MAC ** Maximum allowable concentration (threshold limit). Credit--from: Gerarde, H. W.t Toxicology and Biochemistry ol Aromatic Hydrocarbons j Chron i 'iTeets * .cudy I These (vsten of the j m- of: y.uic ' .is "a; f lice j J Prc - sub j Also. ` decre Th :u dc . , sj tudir. red' . :wa ojtic iOun groin Ane pane j iw I ache | lion j U5U2 i heir. Vproi and ivhi I,0C Pl.v ma\ or i \ is . be JIH 172 May 1978 Hydrocarbon Processing , ,jso are irritated easily by benzene. The lung may de\ -lop t jcherr' 1 pneumonia. | 1 " InlTa. .on of high concentrations causes exhilaration, | ,;ien depression with drowsiness, fatique, dizziness, hcad| j. he and nausea. Ultimately unconsciousness, convulsions | jnd death may occur (see Table 2). er? )ptimisrn ij is much ai ccts, regu. 's content 3me. i mammal, xpired air. >xide. Subto phenol ;h benzene conic add. duce phe- phenylsul,'droquinol d! is con; oxidized ! chronic benzene toxicity. Important as the acute i -ifccts are, much more attention has been directed ref uitlv to chronic lower level exposures (see Table~~T). | These have their primary impact on the blood-1 ormingt iviteni, producing a decrease in various formed elements f I the circulating blood. When all of the major elements f ,re affected (red cells, white cells and platelets) the term | -pancytopenia" is used. This change is often referred to ; ^``aplastic or hypoplastic anemia." I Because some cases of benzene pancytopenia have been | ;rrc:ted to have hyperplastic or "overactive" marrow, it f a probably better to use the term "aplastic anemia" as j x subset of pancytopenia rather than as an equivalent. ) Also, single cell types may be affected to produce anemia, f decreased white cells or a low platelet count.2 t The incidence of these manifestations is very difficult :o determine. Most of the literature reports refer to single | x small groups of patients. In the few series where longii nidinai studies of employes exposed to benzene has exJ reded two years, most have shown a tendency to return ward normal when exposure to benzene ceased. Some .alients however, did show a persistently lowered white :ount or platelet count when compared to a control poup.2 ii itact s. . and 1 the skin rmal skin enzene is ngs, etc.5 Sia >ftuSsuets Anemia. Clinical manifestations of benzene induced j rmeytopema mtVnr non-specific. They ; J.'e presumably related to anemia--easy fatique, head- :. a~he. malaise, dizziness, palpitation and dyspnea on exer- 1 bon (see Table 41. Since the development of anemia is usually gradual these may not be recognized until the I hemoglobin has dropped below 10.0 grams. ; Where low white blood count or low platelet count are | prominent, the clinical findings may be more dramatic | wd specific. Infection is the outstanding feature of a low 'hite count appearing when counts are in the range of j 1.000 - 1,200 (N-4,200 to 10,000) and may lead to death. | Platelet counts of 30,000 or less (N-140,000 to 440,000) J may cause petechiae, purpura or frank bleeding internally externally. Where severe pancytopenia or aplastic anemia develops w a result of benzene exposure, the outcome appears to | ^ similar to that observed in cases of idiopathic aplastic i anemia. About 50 percent will die even with the most i ^odern methods of treatment.2 Where the changes are ^J?s_severe and the individual is removed from further j^'-xposure to benzene, recovery is also the general rule. tcotbo*- Cause lukemia? One of the most controversial ques- ~UJns related to the hematopoietic effect of benzene exsTjfture is whether it results in leukemia. This idea is supr'Sted by the series of case reports of leukemia in indi'`duals with a history of long and heavy exposure to ''nzene in France, Italy and Turkey and the higher inyuence of benzene exposure in groups of acute leukemia - xtients. Good epidemiologic studies relating to the ques`n are lacking however. To date, efforts to produce TABLE 3--Chronic toxicity--hematopoietieg effects PANCYTOPENIA Anemia Granulocytopenia Thrombocytopenia ^Hypoplastic Marrow (Aplastic Anemia) 'Hyperplastic Marrow UNICELLULAR CYTOPENIAS Anemia or Granulocytopenia or Thrombocytopenia TABLE 4--Clinical signs of hematotoxicity 2 To Anemia Easy Fatigue Headache Malaise Dizziness Palpitation External Dyspnea 2 To Granulocytopenia Fever Infection Death 2 To Thrombocytopenia Petechiae Purpura Hemorrhage (internal or external) TABLE 5--Evolution of benzene standard 192Qs 100 ppm for 8-hour day Massachusetts and a few other states 1930s 50 ppm lor 8-hour day (State Standard) 1940 35 ppm for 8-hour day (State Standard) 1942*45 100 ppm lor 8-hour day Federal "War-time Standard" 1946 100 ppm ACGIH--TLV 1947 50 ppm ACGIH-TIV 1948 35 ppm ACGiH-TLV 1957 25 ppm TWA--ACGIH-TLV 1963 25 ppm ceiling value--ACGIH-TLV f969--^. 10 ppm TWA with 25 ppm ceiling--ANSI 1972 'TO ppm TWA with 25 ppm ceiling--OSHA 1974 lOppm TWA with 25 ppm ceiling with 5 ppm action level--NIOSH 1976 1 ppnPwith 5 ppm excursion--NIOSH (proposed) 1977 1 ppm with 5 ppm excursion--OSHA (proposed) leukemia experimentally in animals have been unsuccess ful" --- ------------------------------- - Dr. B. Goldstein in the N.Y. University review sums up his conclusion on the leukemia question as follows: "In summary, occupational exposure to benzene appears casually related to acute myelogenous leukemia and its variants. The question of whether leukemogenesis occurs only after high dose benzene exposure leading to sig nificant bone marrow damage, whether it can result from any degree of a cytopenic stem cell effect, or, less likely, is totally unrelated to the pancytopenic effect of benzene, remains unanswered."2 Benzene regulations. History of the environmental control of benzene in the U.S. helps show how we got where we are, and gives some clues to the outcome (see Table 5). In the U.S., the recognition in the early 1920s that benzene exposure produced pancytopenia led to some states imposing limitations of 100 ppm exposure for an 8-hour day. In a few states this was reduced to 50 ppm and then 35 ppm by the early 1940s. During the war years a federal "war-time standard" raised the limit to 100 ppm with additional excursions permitted for limited periods. By 1946 the first ACGIH TLV of 100 ppm was established and soon became not only a country-wide standard but also a world-wide guideline. 33 Over the next 13 years the level was lowered to 50 ppm 00000 (1947) and then to 35 ppm (1948). In 1957 the TWA was reduced to 25 ppm. In 1963 the 25 ppm level was made a ceiling value. Until March 13, 1978, the standard was based on an ANSI recommendation adopted in 1969 which established the level for benzene at 10 ppm on an 8-hour daily Time Weighted Average (TWA) and a 25 % CESSIJiO ^'Drocarbon Processing May 1978 173 HOW M'~H BENZENE CAUSES CANCER? ppm 15 min. ceiling. This became an official OSHA standard in October 1972. Standard reiterated. The above 1972 standard was again recommended when the 1974 NIOSH criteria docu ment was published.3 This had, however, an "action level" proviso which required certain biological monitoring if the employe was exposed to more than half the TWA (or more than 5 ppm). Environmental monitoring was mandated within six months of the promulgation of the standard and sub sequently based on the number of workers. If the TWA was exceeded, sampling was to be repeated every 15 days until two consecutive surveys demonstrated normal values. Although there was some concern about the extent of the laboratory investigation at time of preplacement ex amination and the decision to relate environmental moni toring to the number of workers, the 1974 standard was generally accepted by those who had practical experience in industry. The post-1976 experience. On Aug. 25, 1976, NIOSH issued a revised recommendation for an occupational ex posure standard for benzene lowering the level to 1 ppm as determined by a 2-hour air sample collected at one liter per minute.'1 The bases lor this change were several epidemiologic studies on rubber workers in the Akron, Ohio, area and a number of case reports from France, Italy and Turkey. It was admitted that in many instances the exposure levels were unknown or, if known, were high (several hundred ppm). But NIOSH took the position that that data established benzene as a carcinogen and this justified setting the exposure level at the lowest de tectable level. On April 29, 1977, OSHA issued an Emergency Tem porary Standard5 which followed the NIOSH recom mendations of August 1976 but cited as its justification for the "imminent danger" category to work of Infante et al. This study became available to OSHA from the NIOSH Division of Surveillance, Hazard Evaluations and Field Studies in early 1977 but was not published in Lancet until July 9, 1977. Leukemia in Akron. The above authors reported that seven cases of acute or chronic mylogenous or monocytic leukemia occurred in 748 workers in a pliofilm operation in Akron and St. Mary's, Ohio, during the period Jan. 1, 1940, and June 30, 1949--an incidence 10 times normal. Moreover, it was alleged that the exposure levels of ben zene were below the limits recommended at the time of their measurement. The implication was that these levels were the lowest reported to date. The ETS was promptly blocked via court action hv 1 OSHA's position. The basic position of NIOSH a. OSHA presented at the hearings are as follows: 1. The evidence from many case reports and seven epidemiologic studies confirms the fact that benzene is * leukemogen (or a cancer producing substance fo. Si> hematopoietic system). 2. It is impossible to prove that a safe level of expose, exists for any leukemogen (carcinogen), hence, exposure must be reduced to the lowest measurable level. 3. The practical realities of establishing an envirr., Tr mental and medical control program for the thousa:;.-:- of people involved in handling gasoline dictate that fi, the moment at least these individuals should be exempted from control. Opponents' position. Opponents of the proposed pc;, manent standard offered the following arguments: The i perse 1. Benzene has not been proven to be a primary car cinogen although it may be a promoter or co-carcino?;at levels well above the present standard. This is sup. ported by the epidemiological studies of Thorpe (Exxrr affiliates in Europe, 1961-70),8 Lloyd (Incidence of Lee- build j know i | here, kemia in Coke Oven Workers)0 and Joyner (Shell 0_ potei Co. employes).10 The Infante study when subjected : close review also tends to support this concept--the actual exposure levels averaged over 100 ppm with excursion : v. A. that probably reached the 1,000 ppm mark on numeroui occasions. _ 2. The concept that there is no threshold for a car- cinogen is fallacious. ' -- ----- 3. The OSHA proposal does not identify the benefits, ^consider reasonable regulatory alternatives or adequate!-. assess the economic impact as required by law. 4. The exemptions proposed under the new permanent standard are arbitrary and illogical: arbitrary becautr they cut off service stations and terminals where exposure are as high as in bulk plants or many producing area' illogical because they are based on the percentage < t benzene in liquids rather than on ppm of benzene vapot in air. j Wit ; -liny's r!Iv v >y leg an a\ trainii our < ; OSH/ i ? Hygit .-.ith : f it's s | indus: i :n Pr Keep informed. That the argument was in vain tvaj j cienti demonstrated when the final version of the permanent ilowi standard dated Jan. 31, 1978, was issued on Feb. 10, 19.8 non, Space does not permit a more detailed discussion : ; -ducr the monitoring or medical requirements, the various as : Th pects of regulatory reporting, protective equipment, train I nds. ing, labeling or record keeping. It suffices to say that < work- in the industry will have to watch developments in thcr : * pi and other areas to stay "on top" of benzene control de { -t. velopments. I to br (Adapted from a paper presented at the Midyear Rf" Thus fining Meeting of API, Toronto, May 8-11, 1978). 4t Jr.^tiu*