Document 7b2Vr2dGwjL4EjEQaordL868

PART TWO: HAZARD ASSESSMENT Forrest B. Thomas. Ph.D. Shell Development Company Houston, Texas 2-1 TOXICOLOGICAL EFFECTS OF BENZENE 2-1.1 Introduction Several excellent reviews of the toxicological properties of benzene have been published recently: Fishbein (Ref. 2-1.9(14]), Synder(Ref. 2-1.9[32J), Aksoy(Ref.2-1.9[I]) and Mehlman (Ref. 2-1.9 [22]). This section will therefore address only selected aspects of the extremely large toxi cological data base available for this compound in order to provide a perspective from which to evaluate other parts of this document 2-1.2 Major Sources of Human Benzene Exposure It must be appreciated that benzene is ubiquitous. According to estimates from the National Research Council (Ref. 2-1.9 [24]), the dietary intake of benzene may be as high as 2S0 Mg daily, perhaps explaining ben zene concentrations of 8-20 ppb in the breath of individu als with no known exposure to this compound. The ben zene content of specific foods is reported to range from 2 ppb for canned beef to 2100 ppb for a boiled egg (Ref. 2-1.9 [23]). Recent results from the National Toxicology Program (Ref. 2-1.9 [25]) indicate that virtually 100% of benzene administered orally is absorbed into the body. Benzene concentrations in ambient air (urban and rural) have been estimated to range from 1-100 ppb (Ref. 2-1.9 [17]). Urban air is reported to contain higher levels than rural air, presumably due to the contribution of automo tive emissions ofbenzene (Ref. 2-1.9 [5]). After reviewing these data, the National Research Council (1980) calcu lated that an individual living in an urban environment containing a mean atmospheric benzeneconcentration of 16 ppb (50 Mg/ m3) who breathes an average of24 mJ ofair per day and absorbs approximately 50% of the dose(i.e., equilibrium state) will absorb approximately 600 Mg of benzene daily. [16 ppb = 50 Mg/ni3 x 24 m3/day x 50% absorption - 600 Mg/day] Benzene is present in cigarette smoke at levels of 47-64 ppm, leading to estimates of the amount of benzene inhaled from a single cigarettes ranging from 10-31 MgUsing the upper estimate, a person smoking two packs (i.e,, 40 cigarettes) per day will absorb up to 992 Mg of benzene (assumes 80% of dose is absorbed; non-equili brium state). [Note: This discussion will not consider the contribution of secondary inhalation of cigarette smoke to the overall benzene exposure of a non-smoker.] [40 cigarettes/day x 31 Mg benzene/cigarette x 80% absorption = 992 Mg/day) The solubility of benzene in water is reported to be 1780 mg/1 at 25 C (Ref. 2-1.9 [2]). In a report issued by the EPA Office of Drinking Water (Ref. 2-1.9 [11]), it was estimated that 97.7% of the population served by public water systems is receiving water either free of benzene contamination or having levels less than 0.5 Mg/1. Esti mates of daily human water consumption range from 0.8 to 2 I /day. Assuming that the average adult consumes 2 liters of water daily, it can be calculated that drinking water with a benzene content of 0.5 Mg/1 would contrib ute 1 Mg of benzene to the average daily dose (100% absorption assumed). [0.5 Mg/1 x 2 1/day = 1.0 Mg/day] Summarizing the above calculations for what are consid ered major sources of human benzene exposure: Non-Smoker Smoker Food Air Cigarettes Water TOTAL 250 Mg/day 600 Mg/day 1 Mg/day 851 Mg/day 250 Mg/day 600 Mg/day 992 Mg/day 1 Mg/day 1843 Mg/day 2-1-3 The Pharmacokinetics of Benzene The primary routes of benzene exposure are considered to be oral and inhalation. While there are data that benzene applied as a liquid or in solution to human skin can be absorbed fairly rapidly (Ref. 2-1.9 [4]), this route is gener ally discounted as being significant because of the rapid evaporation of benzene which effectively reduces the time of skin contact. Recent data from the National Toxicology Program (Ref. 2-1.9 [26]) indicates that virtually Ml of an oral dose of benzene dissolved in vegetable oil is absorbed in rats and mice. It is reasonable to assume that dietary fiber content may reduce both the rate and efficiency of ben zene absorption somewhat by complexing the hydrocar bon, but experimental evidence for this is unavailable. To be conservative, 100% absorption of benzene from food and water was assumed in the above calculations. The respiratory absorption of a hydrocarbon vapor such as benzene is a complex process which has only partially been characterized. Initially, when an animal (or man) is placed into an atmosphere containing benzene vapor, virtually all of the hydrocarbon is absorbed into the blood stream and then distributed to the various tissues of the body. Each tissue will absorb some of the benzene from the blood with some tissues (e.g., those having a high 7 MCD 000001903 content offat) absorbing relatively greater proportions of benzene compared to other tissues. The benzene absorbed by each tissue may be sequestered, released back to the blood unchanged, or processed by the specific metabolic enzymes which characterize the ceils of that tissue. In time, a state ofdynamic equilibrium (often called "steady stale") is established between the air, blood, and other body compartments. As more benzene is absorbed from the air, some of the previously absorbed benzene is exhaled unchanged from the body, some is metabolized to specific derivatives which may be further metabolized even in other distant tissues, and some is removed by the kidneys and excreted in the urine. As the animal approaches steady state, the apparent (i.e., net) absorp tion of the compound into the body can be seen to decrease substantially. As noted in Section 2-1.2 above, conservative estimates of 50-80% absorption have been assumed in calculating the contribution of ambient air and cigarette smoking to the total burden of benzene. Recent data from the NTP (1986) indicate that from a 6 hour exposure to 11 ppm of benzene vapor, the apparent absorption of benzene in mice is 50%, whereas at 1000 ppm, the apparent absorption is 9.7%. Values for sim ilarly exposed rats are 33% absorption at 13 ppm and 15% absorption at 870 ppm. Significant differences in the respiratory characteristics of commonly used laboratory animals exist and greatly influence the amount and rate at which a hydrocarbon vapor is absorbed into the body. Small animals, with their high metabolic rate, must have a relatively large supply of oxygen to the body (Ref. 2-1.9 [34]). While this could have been accomplished evolutionary by development of larger lungs relative to their body size, small animals such as mice and rats instead breathe more rapidly. It might be expected therefore that rodents should reach steady state more quickly than a man exposed to the same vapor concentration, but definitive experimental data in this regard have not been identified. The Lovelace Inhalation Toxicology Research Institute (ITRI), under contract with NTP, have characterized the respiratory parameters of the B6C3F1 mouse and the F344 rat, (unpublished information from the butadiene research program). According to ITRI dat^, the average B6C3FI mouse weighed 27.5 g and breathed 35 ml of air per minute (Le., minute volume); the average F344 rat weighed 392 g and had a minute volume of 289.7 ml. Expressed on a kilogram body weight basis, the minute volume of the mouse is 1274 ml/kg and of the rat is 737 ml/kg. From this perspective, it is understandable why Sabourin et al. (1986) concluded that at similar exposure levels of benzene vapor, mice received 150-200% of the dose received by rats per kilogram body weight. Such differences in respiratory characteristics between species are especially important to exposures where the steady state condition has either not been reached or has been perturbed. Consideration of species differences must be incorporated in the quantitative modeling of animal inha-lation data for estimation of human health risks. In par ticular, ifone assumes a 70-kg man who breathes 7500 ml of air per minute, it can be calculated that the human minute volume/ltg body weight is about one-seventh that of the rat and about one-twelfth that of the mouse. A similar picture of steady-state equilibrium can be developed for benzene absorbed from the gastrointestinal tract. As noted above, recent data from NTP (Sabourin et al.. 1986) suggest that essentially all of a dose of benzene (dissolved in corn oil) administered by gavage is absorbed by rats and mice. Two points should be emphasized with regard to oral exposures. First, the concentration of ben zene in the blood as a result of the administration of an oral bolus is seen to be a transient peak or spike. Dissolv ing benzene in a vehicle such as corn oil essentially results in a retardation in the absorption of benzene into the Mood stream, suchthatallofthe benzeneis eventually absorbed, but it requires a longer period of time. Benzene is metabolized via a number of possible path ways, summarized in Figure 2-1.8 [1]. Available informa tion indicates that benzene must be metabolized in order to exert its toxic effects. However, it is not clear at the present time which of the various metabolic pathways activates benzene to more toxic derivatives and which pathways result in detoxification. Various investigators have suggested that toxicity may be the result of covalent binding of benzene metabolites to cellular macromolecules such as DNA and protein, and a reactive benzene epoxide was postulated to be formed during the metabo lism of benzene by the cytochrome P-450 enzyme system (Ref. 2-1.9 [19]). Recent data, however, call into question whether benzene oxide is in fact formed to a significant degree during the metabolism of benzene (Ref. 2-1.9[20]). Investigators at the Chemical Industry Institute of Toxi cology (Ref. 2-1.9 [16], [18]) suggest that polyphenol derivatives (e.g., hydroquinone and 1,2,4 -benzenetriol) may be responsible for the toxic effects of benzene, per haps via the autooxidative formation of highly reactive radicals which could bind to macromolecular targets. Goldstein et al. (Ref. 2-1.9 [ 15]) suggest that the benzene ring is cleaved metabolically forming muconaldehyde which is also capable of reacting with essential macro molecules. The role of various isomers of diphenol formed by cellular peroxidases, such as myeloperoxidase in the bone marrow in benzene toxicity remains to be evaluated (Ref. 2-1.9 [28]). See Figure 2-1.8 [1]. While it is not yet possible to identify which metabo lite^) of benzene is responsible for the profound cellular toxicity associated with this compound, quantitative risk modeling must recognize that significant qualitative and quantitative differences in the specific metabolic path ways for benzene are seen between species. The phenolic metabolites in the urine of benzene-treated mice, for example, have been found to comprise 50-65% glucuronide conjugates, 26-38% sulfate conjugates, and approximately 5% unconjugated phenol (Ref. 2-1.9 [33]). In contrast. Cornish and Ryan (Ref. 2-1.9 [6]) observed that approx imately 70% of the phenolic metabolites found in the urine of benzene-treated rats were sulfate conjugates. In man, virtually all of the phenolic compounds in the urine following benzene exposure exist as sulfate conjugates until the concentration of phenol in the urine reaches approximately 400 mg/1 when the sulfate pathway has apparently been saturated and products of glucuronide conjugation begin to appear (Ref. 2-1.9 [30]). Such data 8 MCD noonnicirM emphasize that although all three species possess similar metabolic pathways, glucuronidation pralominates in the mouse, whereas sulfation predominates in the rat and man. It should also be noted from these data that the specific metabolites which are formed at high doses may be substantially different from those formed at lower (environmentally relevant?) doses, and as a result, it would not be surprising.to find entirely different toxic profiles under the two conditions. Similar arguments can be made even between tissues with the same animal. The liver, for example, is known to be capable of metabolizing benzene to a wide variety of reactive derivatives, but it is not considered to be a target organ for benzenetoxicity. The reasons for this insensitiv ity are undoubtedly complex, but could be due to the effective shunting of potentially toxic benzene metabo lites into various conjugation pathways which effectively detoxify such metabolites. In contrast, the cells of the bone marrow appear to be exceptionally sensitive to the toxic effects of benzene, reflecting perhaps a greater emphasis on certain activation pathways in marrow cells or less effective detoxification by enzymatic conjugation, or less effective repair of cellular damage. Future research may provide a clearer understanding of the biological basis of such differences. 2-1.4 Toxicity to Blood Formation Toxic effects have long been recognized in the bone mar row of animals and man exposed repeatedly to high levels of benzene vapor(Ref. 2-1.9 [27]). This organ is located in the hollow spaces of various bones and is the primarysite of blood formation. In simple terms, the bone marrow can be viewed as a tissue filling a container of fixed volume, comprising a dynamic mixture of cells which are in various stages of becoming mature red blood cells (RBCs) and white blood cells (WBCs). See Figure 2-1.8 [2]. Most commonly, benzene toxicity is expressed as a decreased formation of various types of blood cells; and therefore, decreased concentrations of these cells are found in the circulating blood (i.e., anemia, pancytope nia, etc.) Severe cases of benzene intoxification may pro gress to a fatal condition where all blood formation essen tially ceases (i.e., aplastic anemia). The mechanism(s) by which benzene affects bone mar row suppression is incompletely understood, but is known to be complex. Much ofthis uncertainty is perhaps due to the biological complexity of the bone marrow itself. In the clinical and toxicological literature, for example, one of the common early manifestations of benzene toxicity is a decrease in the number of circulating lymphocytes (i.e., lymphocytopenia), suggesting that the lymphocytic stem cell line may be particularly sensitive to the cytotoxic/cy tostatic effects of benzene. Of interest, increased circulat ing levels of other cell types may also be seen at the same time as lymphocytopenia (e.g., an increase in the number of eosinophilic granulocytes in the blood). It is not clear whether this increase in circulating eosinophils should most appropriately be considered a direct manifestation of benzene toxicity or simply the compensatory prolifera tion of eosinophilic WBC precursors into the bone mar row space made vacant by the killing of lymphocyte pre cursors by benzene. A similar phenomenon is seen in the anemia of leukemic crisis, which develops when the bone marrow becomes filled with malignant leukemia cells leaving no room for the proliferation of other types of blood cells. It should be noted that in many cases ofsevere bone marrow suppression, other tissues (e.g., liver and spleen) may be observed to reassume their embryonic functions of blood formation (i.e., extramedullary hemopoiesis.) 2-1.5 Benzene and Leukemia A relationship between repeated high-level benzene expo sure and the occurrence of leukemia in man was recog nized as early as 1928 (Ref. 2-1.9 [9]). Acute myelogenous leukemia (AML), and to a lesser extent its variants (e.g., acuteerythroleukemia, acute myelomonocytic leukemia), are the types of leukemia most commonly associated with occupational exposures to high levels of benzene vapor, suggesting that the myeloid /erythroid stem cell line may be particularly sensitive to the leukemogenic effect of benzene. (See Figure 2-1.8 [2]). Other types of leukemia (e.g., acute lymphocytic leukemia and chronic leukemias of various cell types) are less clearly linked to benzene. Leukemia is characterized by the uncontrolled prolifera tion of a specific type of blood cell, and the term was originally derived from the increased number of circulat ing WBCs or leukocytes (i.e., leuk -) in the blood (i.e., -emia). Nonetheless, leukemias are considered by most scientists to be neoplastic diseases of the bone marrow and other blood-forming organs. Leukemias which manifest themselves predominantly in tissues other than the bone marrow are commonly referred to as lympho mas. It should be appreciated that the diagnostic distinc tion between leukemia and lymphoma is an artifact of medical history. The two terms, however, persist in the clinical/epidemiological literature to reflect whether the disease was first diagnosed in the bone marrow or in extramedullary sites. Of significance to epidemiological evaluations, the true incidences of specific leukemias are often clouded since the transformation of leukemia into lymphoma, and vice versa, is commonly encountered in the clinic. The distinction between the leukemias and nonleukemic malignant neoplasms has been the subject of long stand ing debate among scientists, although the most popular paradigm would classify leukemias as cancers. The debate, however, is not complete, and there is consider able evidence to suggest that leukemogenesis and car cinogenesis represent two highly distinct biological pro cesses. Dameshek (Ref. 2-1.9 [7]) and Wasserman (Ref. 2-1.9 [36]), for example, suggested that myelogenous leukemias are specific manifestations of a more general condition which was termed the "myeloproliferative syn drome." According to these authors, this syndrome is manifested not only as leukemia, but also as such neoplas tic conditions as polycythemia vera, aplastic anemia, or agnogenic myeloid metaplasia. Walsh (Ref. 2-1.9 [35]) provides an excellent discussion of myeloproliferative syndrome and notes that leukemia is the terminal compli cation in 10% to 15% of patients with polycythemia vera. 9 MCD 000001905 and that an association of acute leukemia with agnogenic myeloid metaplasia has also been reported. As an alter native mechanism, Dameshek (Ref. 2-1.9(8]) and Sinkovics el al. (Ref. 2-1.9 [31]) have suggested that certain leukemias may be a particular clinical manifestation of autoimmune disease. Also of interest is the report of Battifora et al. (Ref. 2-1.9 [3]) that myelogenous leukemia is "induced" in rats by a dietary mineral deficiency (mag nesium). Such observations tend to emphasize leukemogenesis as a biological process which may be distinct from our current models of carcinogenesis. If that be the case, then the mathematical models commonly assumed to estimate human cancer risk may be highly inappropriate for use with leukemia. Until recently, attempts to induce leukemia/ lymphoma in experimental animals with benzene had been unsuc cessful. However,several investigators have now reported the induction of a lymphoma in the thymus of C57BL mice and derivatives of that strain by a number of chemi cals including benzene. This lymphoma is characterized by the proliferation of T-lymphocytes, and is not believed to be the result ofa direct "carcinogenic''effect ofbenzene on T-cell precursors. Rather this tumor may be the secon dary result of benzene associated activation of a latent endogenous virus (MuLV) which is known to be carried by this strain of mouse. While similar viruses are known to occur in man, available evidence links these human viruses also with leukemias involving the T-lymphocyte. It is significant that it is mytloid, not lymphocytic leuke mias, which have been associated with high level benzene exposures in man. Therefore, the significance, if any, of murine leukemia and of benzene associated viral activa tion to human health is unclear. No evidence of viral involvement in human AML has been identified to my knowledge. In this regard, Cronkite and his colleagues at the Brookhaven National Labora tory (unpublished data) have recently identified AML in CBA/Ca mice treated with benzene. This strain is being characterized in a number of laboratories and may even tually prove to be a suitable animal model for benzene leukemogenesis. 2-1.6 Benzene and Solid Turnon Maltoni and his colleagues at the Institute of Oncology in Bologna have conducted a number of studies on benzene which they summarized in 1985 (Ref. 2-1.9 [21]). Begin ning in 1977, they reported that a wide variety of solid tumors had been observed (Experiment BT901) in Sprague-Dawley rats (13 weeks old at the start of the study) receiving 50 or 250 mgIkg of benzene dissolved in olive oil by gavagedaily, 4-5 days/ week for 52 weeks, then held until spontaneous death. These tumors included car cinomas ofthe Zymbal gland (females only at both doses) and oral cavity (females at high dose only), as well as increases in the incidence of mammary tumors (type unspecified; suggestive increase in females at high dose only) and non-thymic hemolymphoreticular neoplasms (type unspecified; males only at high dose). It should be noted that Maltoni*/ al. report only crude tumor inciden ces from their studies and do not provide results ofstatis tical evaluations of their data. In a separate experiment (BT902/906), Maltoni et al. administered benzene in olive oil by gavage at a daily dose of 500 mg!kg to 7-week-old Sprague Dawley rats, 4-5 days /week, for 104 weeks, which were then held until spontaneous death. According to the authors, under the conditions of this bioassay, benzene caused an increased incidence of a number of tumors; Zymbal gland carcinomas (equally distributed among males and females) Carcinomas of the oral cavity (equally distributed among males and females) Carcinomas of the nasal cavities (suggestive increase in males only) Skin carcinomas (males only) Forestomach dysplasias (males and females) and forestomach tumors (females only) Hepatocarcinomas (reported by authors but do not appear to be increased to this reviewer) Liver angiosarcomas (males and females) Increase in the number of other malignant tumors, some of which are extremely rare in the SpragueDawley rat, such as lung adenocarcinomas (tumor observed in one male) and soft tissue liposarcomas (tumor observed in two males). In addition, benzene caused a decrease in circulating WBCs, due primarily to a decrease in circulating lympho cytes (males and females) when determined during the 84th week of the experiment. Increases in the incidence of mammary tumors and non-thymic hemolymphoreticular neoplasms (seen at the lower doses given in BT 901) were not seen in this study. Maltoni et al. suggest that the differences between the results ofexperiments BT901 and BT 902/906 must be correlated to the different doses (daily dose and length of treatment) of administered ben zene, rather than to differences in the age ofthe animals at the start of each experiment. The technical basis for this statement, however, is not clear. Once again it should be noted that the conclusions from this study are subject to technical debate because of the lack of statistical evaluation. Maltoni et al. began in 1983 a study using 6-week-old Wistar rats (BT907) and Swiss mice (BT908) exposed by gavage to benzene in olive oil at a daily dose of 500 mg/kg, 4-5 days/week for 104 weeks (rat) and 78 weeks (mouse). Preliminary information from these studies was included in Maltoni*/ al.. 1985. In the Wistar rat, Zymbal gland carcinomas (male and female), non-thymic hemo lymphoreticular neoplasias (suggestive increase in fe males), and an increase in total malignant tumors (males and females) were observed. In the Swiss mouse, Zymbal gland dysplasias (males and females) and carcinomas (males only), mammary carcinomas (females only), pul monary ademonas (males and females), and an increase in total-malignant tumors (suggestive increase in females) are reported. Results of statistical evaluations are not reported. MCD 000001906 10 The National Toxicology Program has conducted two-year The studies of Maltoni et al. (1985) and the National >xicology and carcinogenesis studies of benzene in F344 Toxicology Program (1986) have demonstrated without , ats and B6C3F1 mice. Male F344 rats were administered question that high level benzene exposures can produce benzene in com oil by gavage at daily doses of 0, SO, 100, an increased incidence of a wide variety of tumors in rats or200 mg/kg, 5 days/week, 103 weeks. Female F344 rats and mice. It is somewhat more complicated, however, to and male and female B6C3F1 mice were administered conclude that these effects are due to a direct carcinogenic benzene in com oil by gavage at daily doses of 0,25, SO, or effect of benzene on these highly diverse tissues, and that 100 mg/kg, S days/ week, 103 weeks. In rats, increased these animal data are appropriate for quantitative risk tumor incidences were seen forthe Zymbal gland (males modeling for extrapolation to environmentally relevant and females), oral cavity (males and females), and skin levels of benzene exposure in man. (males only). In the benzene treated mice, increased tumor incidences were reported for Zymbal gland (males Before current models can be applied, three confound ing factors must be considered further and females), lymphoma, (males and females), lung (males and females), Harderian gland (males, marginal in females), ovary (females), and liver (males, marginal in females) (NTP, 1986). Maltoni and his colleagues have also evaluated the car cinogenic potential of benzene vapor via inhalation. In experiments BT4004/4006,13-week-old pregnant female Sprague-Dawley rats (gestation day 12 at start of study) were exposed to benzene vapor at the following concen trations: 200 ppm/4 hours day, 5 days/week, 7 weeks; then exposed at 200 ppm, 7 hours/day, S days/week, 12 weeks; then at 300 ppm, 7 hours/day, S days/ week, 85 weeks, giving a total of 104 weeks of benzene exposure (Group 1). These animals were then observed until spon taneous death. The offspring from the above rats were As discussed above, recent data from the National Toxicology Program (1986) indicated that all of the dosages of benzene utilized in the above cancer bioas says have been at levels where the usual metabolic pathways may have been "wholly or partially satu rated." Therefore, it is possible that benzene in these animals was forced into metabolic pathways which would not normally be significant in defining the toxic profile of this compound. The role of murine leukemia virus in the development of thymic lymphoma in the B6C3F1 mouse was dis cussed above. It is not clear whether or not current risk modeling techniques are appropriate for virally med iated neoplasia. exposed to benzene vapor as follows: transplacentally Benzene is well known to be immunosuppressive, such during the prenatal period (Note: gestation in the rat is approximately 21 days); by inhalation and probably by that it is possible that all of the tumors reported by Maltoni et al. (1985) and by NTP (1986) are the secon gestion (via milk) during weaning; and afterward by inhalation as for the parental animals (Group II). One dary result of benzene-induced inability of the animal to monitor and destroy spontaneously occurring trans group of offspring was removed from further exposure formed cells. Certainly, this type of mechanism would after the 15th week of the above treatment schedule explain the occurrence of tumors of the oral cavity in (Group HI). The offspring in Groups II and III were also the NTP benzene inhalation study, as well as the held for observation until spontaneous death. The results development of carcinomas of the skin in the benzene in these three treatment groups will be discussed separately. Among the benzene treated pregnant rats (Group I), gavage studies. 2-1.7 Conclusions suggestive increases in Zymbal gland carcinoma (3/53 = As discussed above, the biology of leukemia, bone mar 5.7% in treated rats vs. 1/60 = 1.7%) and malignant row function, and carcinogenesis as relates to benzene mammary tumors (6/54 = 11.1% vs. 2/60 = 3.3%) were exposure is extremely complex. The methods of quantita seen. Increases in other types oftumors were seen near the tive risk modeling have only recently been applied to end of the study but are of unclear significance due to the biological phenomena such as carcinogenesis, and be low number of surviving animals. cause it is such a young science, it is not surprising that Among the offspring exposed to benzene vapor for 15 current models of quantitative risk extrapolation depend weeks (Group III), an increased incidence of Zymbal on assumptions which are well recognized as being sim gland carcinomas (male and female), oral cavity carcino plistic in the extreme. Nonetheless, such methods are mas (female, suggestive in males), carcinomas of the nasal now, and will continue to be, used to assist in the formula cavity (female), malignant mammary tumors (suggestive tion of human health policy and regulation, since a more in female), and hematomas (female) were observed. In the definitive understanding of the mechanisms of benzene offspring exposed to benzene vapor for 104 weeks (Group associated toxicity and the relevance ofsuch mechanisms II), an increased incidence of Zymbal gland carcinoma to human health may not be sufficiently developed in the (males and females), carcinomas of the oral cavity near future to offer an acceptable alternative to the risk (female, suggestive in male), nasal cavity carcinomas manager. (reported by the authors, but considered only suggestive It is imperative that those who perform risk modeling bjahis reviewer), and malignant mammary tumors (sug recognize the limitations of our biological understanding gestive in females) were reported. Increased incidences of and document fully the various simplifying other tumors were seen near the end of the study, but assumptions made and resulting uncertainties when esti 'in the low number of surviving animals makes difficult mating byextrapolation the risks to human health due to ue interpretation of the biological significance of such environmental benzene exposures. It is also important observations. that as new biological understanding becomes avail- 11 MCD 000001907 able the risk models be improved and previous decisions be reevaluated. In 1980, the EPA Office of Water Regulations and Standards (Ref. 2-1.9 [ 13]) issued an ambient water qual ity criterion for benzene of 0.66 #ig/l which, at their calculations, corresponded to a risk of one additional cancer for every million people exposed for their lifetime to this concentration of benzene in their drinking water. This value was in fact based on a quantitative risk assess ment performed in 1978 by the EPA Carcinogen Assess ment Group (CAG) (Ref. 2-1.9 [12]) using occupational leukemia data from three epidemiological studies of workers exposed to high levels of benzene vapor. The 1980 water criterion assumes several simplifications which would be questioned on the basis of our present know ledge of benzene: The CAG risk calculation assumed that the relative risk of leukemia is "independent of the duration" of exposure, but is simply dependent on the total expo sure. That is, CAG assumed that exposure to 1 ppm of benzene vapor for 10 years (equivalent to 10 ppmyears) would have the same toxicity as would exposure to 3650 ppm for I day (also equivalent to 10 ppmyears). This does not agree with the available clinical experience with benzene. During the past few months, better estimates of the actual benzene exposures seen by the cohort used in one of the critical epidemiological studies modeled by CAG have become available. These suggest that the levels of benzene exposure assumed by CAG were substantially lower than those actually experienced by the worker, and that as a result, the calculated risk is overestimated by the CAG calculations. The authors of the water quality criteria document assumed that benzene is as equally toxic by the oral route as by the inhalation route. This simplification fails to recognize that blood drains from the gastroin testinal tract to the liver which is the primary site of benzene metabolism. In contrast, inhaled benzene is distributed throughout the body prior to metabolism by liver enzymes. The authors of the water quality criteria document did not consider fully the relative contribution of the multi-media sources of normal benzene exposure. Using the formulas in the criteria document, it is inter esting to note that while the leukemia risk associated with the daily ingestion of water containing 0.66 jtg/1 of benzene (1.32 pg/day) is 1 per million, the risk associated with eating a boiled egg every day is 79.5 per million. 12 000001908 tfCD FIGURE 2-1.8 [1] MAMMALIAN METABOLISM OF BENZENE OH Benzene _ Hydroxy- _ cyclohexadienyt Radical OH Phenol c CHO CHO Muconaldehyde COOH CCOOH Muconic Acid CO2 FIGURE 2-1.8 [2] SCHEMATIC OF BLOOD CELL DIFFERENTIATION AND MATURATION Multipotentii Stem Cell Myeloid/Erythroid Stem Cells Granulocytic WBCs Megakaryocytic Stem Cell--Platelet -Erythroid Stem Cell--Mature RBC Macrophage/Monocytic Stem Cell I----------- Macrophage/Monocyte Lymphocytic Stem Cell T-Lymphocytes ----------- B-Lymphocytes Other Lymphocytes MCD 000001909 13 2-1.9 REFERENCES: TOXICOLOGICAL EFFECTS OF BENZENE [1] Aksoy, M. "Benzene as a Leukemogenic and Car [18] Irons, R. D. "Quinones as Toxic Metabolites of cinogenic Agent", Amer. J. Indus. Med. 8:9-20, Benzene", J. Toxicol. Environ. Health 16:673-678, 1985. 1985. [2] Andelman. J. B., Suess, M. J. "Polynuclear Aro [19] Jernina, D., Daly, J., Whitkop, B., Zaltzman- matic Hydrocarbons in the Water Environment", Nirenberg, P., Udenfriend, S. "Role of Arene Bull. WHO43:479-508, 1970. Oxide-Oxepin System in the Metabolism of Aro 13] Battifora, H. A., McCreary, P. A., Hahneman,B. matic Substrates. 1. In Vitro Conversion of Benzene M,, Laing, G. H.. Hass, G. M. "Chronic Magne Oxide to a Premercapturic Acid and a Dihydro- sium Deficiency in the Rat. Studies of Chronic diol". Arch. Biochem. Biophys. 128:176-183, 1968. Myelogenous Leukemia", Arch. Pathol. 86:610 ft., [20] Johansson, I., Ingelman-Sundberg, M. "Hydroxyl 1968. Radical-Mediated, Cytochrome P-450-dependent [4] Blank, 1. H., McAuliffe, D. J. "Penetration of Ben Metabolic Activation of Benzene in Microsomes zene through Human Skin", Invest. Dermatol. and Reconstituted Enzyme Systems from Rabbit 85:522-526, 1985. Liver." J. Biol. Chem. 258:7311-7316, 1983. [5] Brief, R. S,, Lynch, J., Bemath, T., Scaia, R. A., [21] Maltoni, C., Conti, B., Cotti, G., Belpoggi, F. "Benzene in the Workplace", Amer. Ind. Hyg. "Experimental Studies on Benzene Carcinogenicity Assn. J. 41:616-623, 1980. at the Bologna Institute of Oncology: Current [6] Cornish, H., Ryan, R. "Metabolism of Benzene in Results and Ongoing Research." Amer. J. Indus. Nonfasted, Fasted, and Aryl-hydroxylase Inhibited Med. 7:415-446,1985. i Rats." Toxicol. Appl. Pharmacol. 7:767-771,1965. [22] Mehlman, M. A., ed. Benzene: Scientific Debate. [7] Dameshek, W. "Some Speculations on the Myelo Proceedings of the International Conference on proliferative Syndrome", (editorial) Blood 6:372 Benzene Sponsored by the Collegium Ramazzini, ff.. 1951. New York City, November 3-4,1983, Alan R. Liss, [8] Dameshek, W. "Certain Forms of Leukemia as New York, 1985. Immunoproliferative Disorders." In Carcinogene [23] National Research Council. Drinking Water and sis: A Broad Critique, Williams and Wilkins Com Health, Vol. 3, National Academy of Sciences, pany, Baltimore, Maryland, pp 141 ff., 1970. Washington, D.C., 1980. j [9] Delore, P., Bergamano, J. "Leucemie Aique en [24] National Research Council. Health Effects ofBen Cours d'lntoxication Bezenique", J. Med. Lyon zene: A Review, National Academy of Sciences, 9:227-233,1928. Washington, D.C., 1976. [10] Environmental Protection Agency, Ambient Water [25] National Toxicology Program. Toxicology and Quality Criteriafor Benzene. (PB81-117293), 1980. Carcinogenesis Studies of Benzene (CAS No. 71- [11] Environmental Protection Agency, Benzene: Occur 43-2) in F344/N Rats and B6C3F1 Mice (Gavage rence in Drinking Water, Food, andAir, (Prepared Studies), Technical Report No. 289 (galley draft). by JRB Associates), 1983. National Toxicology Program, Washington, D.C., [12] Environmental Protection Agency, Carcinogen February, 1986. Assessment Group's Final Report on Population [26] Sabourin, P. J., Chen T-H, Lucier, G., Bimbaum, Risk to Ambient Benzene Exposures, (P83-OI34), L. S., Fisher,E,, Henderson, R. F. "Effect of Dose 1978. on the Absorption and Excretion of 14C-Benzene [13] Environmental Protection Agency, "Notice of Administered Orally or by Inhalation in Rats and i Water Quality Criteria Documents", FederalRegis Mice." Toxicol. Appl. Pharmacol. (Submitted for ter 45:79326, November 28,1980. publication), 1986. [14] Fishbein, L. "An Overview of Environmental and [27] Santesson, C. G. "Uber Chronische Vergiftung mit Toxicological Aspects of Aromatic Hydrocarbons. Steinkohlentheerbenzin; vier Todefalle." Arch. I. Benzene." Science Total Environ. 40:189-218, Hyg. Berl. 31:336-376, 1897. 1984. [28] Sawahata, T., Rickert, D.E., Greenlee, W. F. [15] Goldstein, B. D., Witz, G., Javid, J., Amuroso, M. "Metabolism of Benzene and its Metabolites in A., Rossman, T., Wolder, B. "Muconaldehyde, a Bone Marrow." In Toxicology of the Blood and Potential Toxic Intermediate of Benzene Metabo Bone Marrow, Irons R. D,, ed.. Raven Press, New lism.", Adv. Exp. Biol. Med. 136A:331,1981. York, pp. 141-148,1985. [16] Greenlee, W. F., Sun, J. D., Bus, J. S. "A Proposed [29] Selling, L. "Benzol as a Leucotoxin. Studies on the Mechanism of Benzene Toxicity: Formation of Degeneration and Regeneration of the Blood and Reactive Intermediates from Polyphenol Metabo Haematopoietic Organs." Johns Hopkins Hosp. lites.", Toxicol. Appl. Pharmacol. 59:187-195, Reports 17.83-148,1916. 1981. [30] Sherwood, R. J. "The Interpretation of Monitoring [17] International Agency for Research on Cancer Results", Ann. Occup. Hyg. 15:409-421, 1972. (1ARC), IARC Monographs on the Evaluation of - [31] Sinkovics, J. G., Trujillo, J. M., Pienta, R. J., Carcinogenic Risk of Chemicals to Humans, Lyon, Aheam, M. J. "Leukemogenesis Stemming from France, 29:93-148, May, 1982. Autoimmune Disease", In Genetic Concepts and 14 ,001910 &CD 2.1.9 REFERENCES: TOXICOLOGICAL EFFECTS OF BENZENE (Continued) Neoplasia. Williams and Wilkins Company, Balti more, pp 138 ff., 1970. [32] Snyder, R. "The Benzene Problem in Historical Perspective", Fund. Appl. Toxicol 4:692-699,1984. [33] Snyder, R. "Relation of Benzene Metabolism to Benzene Toxicity." In Symposium on Toxicology of Benzene and Alkylbenzenes. Braun, D., ed.. Industrial Health Foundation, Pittsburgh, pp. 4453, 1974. [34] Tenney, S. M. "Respiration in Mammals." In Duke's Physiology of Domestic Animals, 9th Edi tion, Swenson, M. J., ed., Cornell University Press, Ithaca, New York, pp. 175-209,1977. [35] Walsh, J. R. "Polycythemia Vera: Diagnosis, Treatment, and Relationship to Leukemia", Geriat rics 33:61-69, 1978. [36] Wassemian, L. R. "Polycythemia Vera -- Its Course and Treatment' Relation to Myeloid Meta plasia and Leukemia", Bull. N. Y. Acad. Med. 30:343 ff., 1954. 15 MCD 000001911 2-4 NONDRINKING-WATER EXPOSURE David H. Powell, Ph.D. William A. Tucker, Ph.D. Environmental Science and Engineering. Inc. GatnesviUe, Florida 2-4.1 Occurrence 2-4.1(l) Food Data on the occurrence of benzene in food are limited. Mara and Lee (Ref. 2-4.4 [11]) reported that benzene occurs naturally in fruits, fish, vegetables, nuts, dairy products, beverages, and eggs. These authors report con centrations ranging from 2 micrograms per kilogram (Mg/kg) for canned beef to 2,100 Mg/kg for eggs. Cooked meats are reported to have higher benzene levels than raw meats, and it is postulated that the increased benzene levels observed after cooking meats is due to the break down of aromatic amino acids such and tyrosine (Ref. 2-4.4 [5]). Low levels (< 10 Mg/kg) of benzene in food could be due to a partitioning from the ambient levels of atmospheric benzene. The high levels observed in eggs indicate an intrinsic mechanism for the biochemical formation of benzene. Table 2-4.3 [1] summarizes the reported occur rence of benzene in foods. 2-4.i(2) Air The materials balance for benzene indicates that 93 per cent of environmental releases of benzene are to the atmosphere, and three-quarters of this release is asso ciated with fuel combustion (Ref. 2-4.4 [5]). As a result of these emissions, it is not surprisingthat ambient air levels of benzene have been correlated with traffic volumes (Ref. 2-4.4 [2]). Atmospheric benzene is ubiquitous; remote regions have measured concentrations usually ranging from 1 to 3.3 micrograms per cubic meter Oig/m3). Higher levels are observed in urban and industrial environments. Table 2-4.3 [2] summarizes benzene concentration ranges and averages for various atmospheric environments. Indoor benzene levels have been studied in industrial settings. Inside chemical plants, reported concentrations range from 2,000 to 10,000 Mg/m3. The current Occupa tional Safety and Health Administration (OSHA) regula tion on workplace exposure is 32,000 Mg/m}(10 parts per million, ppm) for the time-weighted average (TWA) con centration for an 8 hour exposure with a peak maximum concentration of 160,000 Mg/m3 (30 ppm) for any 13 minute period during an 8 hour day (Ref.2-4.4 [1]). Indoor benzene levels in residences have been reported by Sample and Gilbert (Ref. 2-4.4 [14]) to have a median value of 13.0 Mg/m3 and an arithmetic mean of 2S.8 Mg/m3 for 333 nighttime observations of benzene. There is a minimal correlation between indoor concentrations and outside ambient levels. The impact of smoking on indoor benzene concentrations appears to be important 60 in households containing one or more smokers. These households exhibit at least 30 percent greater concentra tions than households of nonsmokers. One cigarette can generate approximately 90 micrograms (Mg) of benzene (Ref. 2-4.4 [5]). The portion of the benzene in the main stream smoke is predominantly absorbed by the smoker and not exhaled. Mainstream smoke is that which the smoker inhales; however, the sidestream smoke which is released to the room often contains twice the quantity of some chemicals as the mainstream smoke (Ref.2-4.4 [6]). Therefore, of the 90 Mg of benzene released from each cigarette, possibly 60 Mg is released to the smoker's envi ronment through the sidestream smoke. 242 Exposure Reported benzene concentrations in foods do not involve all food groups. It is not known how representative these concentrations are of the concentrations in foods in general. Dietary intake of benzene has been estimated to be as high as 250 micrograms per day (Mg/day) from beef, eggs, and rum alone (Ref. 2-4.4 [13]). Assuming that the average adult male weighs 70 kg, an intake of 250 Mg/ day would be equivalent to 3.6 micrograms per kilogram per day (Mg/kg/day). In the absence of further data, Letkiewicz et al. (Ref. 2-4.4 [8]) assumed the dietary intake of benzene was at that level. Gilbert et al. (Ref. 2-4.4 [5]) estimated the ingestion due to only those foods with reported benzene concentrations (i.e., butter, cooked beef, eggs, and haddock), resulting in a daily ingestion intake of 31 to 108 Mg/day. Exposure to benzene in the atmosphere is highly varia ble; reported levels range between low parts-per-billion values in outside air to low parts-per-million in certain industrial settings. Median air concentrations of benzene have been calculated by Brodzinsky and Singh (Ref. 2-4.4 [3p for rural/remote areas (4.5 Mg/m3), urban/suburban areas (8.9 Mg/m3), and source-dominated areas (9.6 Mg/m3). Thus, in urban/ suburban areas, people inhale approximately 180 Mg of benzene each day (at 20 cubic meters, m3, of air inhaled each day). As a comparison, a one-pack-per-day smoker inhales approximately 600 Mg/day of benzene from mainstream smoke. Exposure by these routes is substantia], but highly variable in the general population. Average annual atmospheric benzene concentrations and the size of exposed populations have been calculated by Mara and Lee (Ref. 2-2.4 [1 ]]) based on air dispersion models. Approximately half of the population of the United States was estimated to be exposed to average atmospheric benzene concentrations between 3.5 and 13 Mg/m3. A newborn, formula-fed infant's respiratory intake of benzene can be expected to range from 1.0 to 2.2 Mg/kg/day, whereas the intake of a nonsmoking, 70kilogram (kg) adult male may vary between 1.3 to 360 Mg/kg/day, depending on ambient benzene concentra tions (Ref. 2-4.4 [8]). MCD 000001912 TABLE 2-4J [1] Foods Reported to Contain Benzene Fruits* Apple Citrus Fruit Cranberry and Bilberry Currants Guava Pineapple Strawberry Tomato Nuts* Filbert, roasted Peanut, roasted Macademia Nut Vegetables* Bean Leek Mushroom Onion, roasted Parsley Potato Soya Bean Trassi, cooked Dairy Products Butter (0.5 Mg/ kg)b Blue Cheese* Cheddar Cheese* Other Cheese* * Ref. 2-4.4 [16] 6 Ref. 2-4.4 [15] ` Ref. 2-4.4 [13] ' Ref. 2-4.4 [12] ' Refs. 2-4.4 [9], [10] ' Irradiated and non-irradiated haddock, respectively. Ref. 2-4.4 [7] `Ref. 2-4.4 [II] Source: Ref. 2-4.4 [5] Meat, Fish, and Poultry Cooked beef (2 to 19 ng/kg)c Chicken (<10 Mg/kg)* Egg, hard boiled (300 to 1,900 Mg/ kg)1 Egg, uncooked (2100 Mg/ kg)h Haddock (100 to 200 Mg/ kg)r Lamb, heated (<10 Mg/ kg)* Mutton, heated (<10 Mg/kg)d Veal, heated (<10 Mg/kg)d Beverages Cocoa* Coffee* Jamaican Rum (120 uglkgf Tea* Whiskey* TABLE 2-4J [2] Summary of Benzene Occurrence in Air Environment Benzene Concentration (fig/in') Remote (Range) Urban (Range) Residential -- Remote from Traffic (Average) Near Chemical Plant (Average) Near Refineries (Average) Gas Stations (Range) 1 to 3.3 4 to 160 4.5 14 9 <1 to 32 Sources: Refs. 2-1.4 [5], [8] 61 mcd 000l913 2-4.4 REFERENCES: NONDRINKING-WATER EXPOSURE [1] American Conference of Governmental Industrial Hygienists (ACGIH), Threshold Limit Values for Chemical Substances and Physical Agents in the Work Room Environment, Cincinnati, Ohio, 1985. [2] Battelle, Environmental Monitoring -- Benzene, Battelle Columbus Laboratories, Columbus, Ohio, 1979. [3] Brodzinsky, R., Singh, H. B. Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data, prepared by SRI International, Menlo Park, California for Environmental Scien ces Research Laboratory, Office of Research and Development, U. S. Environmental Protection Agency, Research Triangle Park, No. Carolina, EPA-440/4-79-029b, 1982. [4] Drill, S., Thomas R. Environmental Sources of Benzene Exposure: Source Contribution Factors, Prepared by Mitre Corporation for the U. S. Envi ronmental Protection Agency, EPA-570/9-79-004, 1979. [5] Gilbert, D., Byme, M., Harris, J., Steber, W., Woodruff, C. An Exposure and Risk Assessment for Benzene, Final Draft Report, Prepared by Arthur D. Little, Inc. for U. S. Environmental Pro tection Agency Office of Water and Waste Man agement, Washington, D. C. EPA Contract No. 68-01-5949, 1982. [6] Johnson, W. R., Hale, R. W., Nedlock, J. W,, Grubbs, H. J., and Powell, D. H. "The Distribution of Products between Mainstream and Sidestream Smoke", Tobacco Science 17:141-144,1973. [7] Leibich, H. M., Koenig, W. A., Bayer, E. "Analysis of the Flavor of Rum by Gas-Liquid Chromato graphy and Mass Spectrometry",/. Chromato. Sci. 8:527-533, 1970. [8] Letkiewicz, F., Johnston, P., Macaluso, C., Elder, R., Yu,W., Bason, C. Occurrence of Benzene in Drinking Water, Food, and Air, Prepared by JRB Associates for U. S. Environmental Protection Agency Office of Drinking Water, Contract No. 68-01-6388,1983. [9] MacLeod, A. J., Personal Communication to H. I. Chinn, (Cited in Drill, S., Thomas, R., Environ mental Sources ofBenzene Exposure: Source Con tribution Factors, 1979), 1977. [10] MacLeod, A. J., Cave, S. J. "Variations in the Volatile Flavour Components of Eggs", /. Sci. FoodAgric. 27:799-806, 1976. [11] Mara, S. J., Lee, S. S. Assessment ofHuman Expo sure to Atmospheric Benzene, U. S. Environmental Protection Agency, Research Triangle Park, No. Carolina, EPA-450/3-78-031, 1978. [12] Merritt, C. "Qualitative and Quantitative Aspects of Trace Volatile Components in Irradiated Foods and Food Substances", Radiation Res. Rev. 3:353368, 1972. [13] National Cancer Institute (NCI). On Occurrence, Metabolism, and Toxicity Including Reported Car cinogenicity of Benzene, Summary Report, Wash ington, D. C., 1977. [14] Sample, C. J., Gilbert, D. indoor Ambient Benzene Concentrations: An Assessment ofFactors Related to Indoor Air Quality. American Petroleum Insti tute, Washington, D. C., 1985. [15] Siek, T. J., Lindsey, R. C. "Semiquantitative Anal ysis of Fresh Sweet Cream Butter Volatiles", Jour nal of Dairy Sciences 53(6):700-703,1970. [16] Van Straiten, S., Editor. Volatile Compounds in Food, 4th Edition, Supplement 1, Central Institute for Nutrition and Food Research TNO, Zeist, The Netherlands, 1977. 62 MCD 00000191-4 ATTACHMENT 4 DPL1T - PHENOL (9CI) 12/01/80 Accidental spillage of phenol caused contamination of wells in a rural area. Human illness characterized by diarrhea, mouth sores, dark urine and burning of the mouth was reported. Estimated phenol intake was 10 to 240 mg/day. Physical and laboratory examinations 6 months after the exposure revealed no residual abnormality in exposed.persons (75).* HSDB - PHENOL 04/16/87 ENVIRONMENTAL FATE/EXPOSURE SUMMARY - ENVS (1) NOTE: This is a summary of environmental fate data included in this HSDB record. Phenol is a common and important industrial chemical and enters the environment in wastewater and spills connected with its use in resins, plastics, adhesives, or other uses. It is frequently found in wastewater from other commercial processes. Once in the environment, its primary removal mechanism is biodegradation which is generally rapid (days). since phenol is a benchmark chemical for biodegradability studies, there is a large body of information on its degradation which concludes that phenol rapidly degrades in sewage, soil, freshwater and seawater. Acclimation of resident populations of microorganisms is rapid. Under anaerobic conditions degradation is slower and microbial adaptation periods longer. Biodegradation is rapid enough that phenol may degrade in soil and subsoil before reaching groundwater. Monitoring studies support these conclusions: phenol is rarely found in drinking water, and the levels found in rivers and lakes tend to be quite low. Exceptions are spills in which high phenol concentrations are toxic to microorganisms or when soil residence time is very short; then phenol will collect in groundwater and may remain for some time. Phenol is very soluble in water and poorly adsorbed on soil, clay, or aquifer material. Phenol's evaporation rate from water is low although it has an intermediate vapor pressure. This latter fact allows evaporation from spills on soil to occur. Phenol will not bioconcentrate in the food chain. However, there is experimental evidence that phenol metabolites may bioconcentrate in fish. In air, phenol would be expected to photolyze and react with hydroxyl radicals. It should also photodegrade in water, especially humic waters, and is catalytically degraded on sand. Inhalation exposure to phenol is largely restricted to occupational environments. General exposure will occur through the use of disinfectants and cleaners containing phenol. (SRC) HSDB - PHENOL 04/16/87 (1) Phenol is degraded by bacteria, fungi, yeast and algae commonly found in the environment(1-17). Degradation is to carbon dioxide or methane and carbon dioxide in aerobic and anaerobic systems, repectively(1-17). Phenol is a benchmark chemical for biodegradability studies and therefore there are a large number of studies done in a variety of systems(SRC). Degradation is generally rapid and acclimation is rarely required(1-17). Removal in activated sludge reactors is frequently better than 90% with retention of 8 hours(4). Partial inhibition has been noted at concentrations as low as 50 ppm(5). Utilization is also very high in anaerobic reactors although acclimation periods are longer and degradation slower - about 2 weeks(6,7). The results of die-away tests in rivers and lakes or in water in contact with soil-report complete degradation in 1-2 days(8,9,10,11,12,14). Degradation is somewhat slower in salt water and a ' half-life of 9 days has been reported in an -estuarine river(13,17). - Degradation in soil is completed in 2-5 days even in subsurface soils(15). MCD 000001915 detected in finished drinking water in US(4). (GROUNDWATER) Maximum of 1130 ppm in 9 wells in Wisconsin after a spill(5). 6.5-10,000 ppb in 2 aquifers 15 months after completion of coal gasification project(6). HSDB - PHENOL 04/16/87 [PATTY. INDUS HYG & T0X 3RD ED V0L2A,2B,2C 1981-82] (1) ...CONCN OF ABOUT 4 PPM WILL IMPART A DECIDED PHENOL TASTE TO VEGETABLES & FRUIT GROWN WITHIN RADIUS OF MORE THAN A MILE FROM A PLANT WHERE SUCH VAPORS ESCAPE. HSDB - PHENOL 04/16/87 (1) Calculated acceptable daily intake =0.1 mg/kg. 000001916 MCD REFERENCES 1. Benzene- in Florida Ground Water; Florida Petroleum Council, October 1986. 2. National Research Council (1980). 3. International Agency for Research on Cancer, IARC Monographs on Evaluation of Carcinogenic Risk of Chemicals to Humans, May 1982. 4. Indoor Ambient Benzene Concentrations: An Assessment of Factors Related to Indoor Air Quality; C. J. Gilbert, API-1985. 5. EPA Health Advisory, 1985. 6. Penetration of Benzene Through Human Skin; I. H. Blank & D. J. McAuliffe; J. Investigative Dermatology, 85, 522-26, 1985. MOD 000001917