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T3XlCflLOGY UPDATES M. ile BENZENE Synonyms: benzol, cyclohexatriene. chronically exposed to 300 ppm benzene. Maltoni and Scarnato" benzen Pfeifer e an in d Irornast zs liver found microsomes. that hydro- )li. Odor: characteristic strong aromatic recently reported the induction of quinone and its oxidation product. odor. Zymbal gland tumors ( 10 per 130) benzoquinone,. inhibited lymphocyte nd Molecular weight: 78.1 1. and an increased incidence of hemo- mitogenesis in culture at concentra- ni- Molecular formula: C6H6. 9- TLV: 1 0 ppm; 3 0 mg m-3. lymphoreticular ( 7 per 130 versus 1 tions that did not produce cytoper 130 in controls) and mammary toxicity. These effects of lymphocyte of to Vapor pressure: 100 mmHg (5 20 "C. Vapor density: 2.7 (air = 1). gland tumors i l l per 130 versus 1 blastogenesis were observed to be per 130) in Sprague Dawley rats similar to those of known microtubule 3- Rat oral LDSo: 0.9-6.0 g kg-', depend- repeatedly administered benzene in inhibitors and studies have, in fact, ing on age and strain. olive oil by gavage (50 or 250 mg revealed these quinones to be potent Di Acute toxicity: The characteristic per kg per day) for 52 weeks. inhibitors of microtubule assembly iiz 3n pattern of acute benzene intoxication Numerous studies indicate that vitro. z6,27 n- is stimulation of the central nervous repeated exposure to benzene in n i c e , Ststus: A proposal by OSHA to reduce 8. system followed by respiratory de- rats or rabbits results in a dose-liepen- the TLV for beitzerit: from I O ppm IO ite P16 pression, loss of consciousness and d eath. Human toxicity: Almost all studies of dent !j..mphoc:"~topcnia.'2"3.'4 Repeated subcutaneous administration of benzene (44-660 mg per k y per day) ! ppm was recen:!y overruled by the US Supreme Court. benzene exposure in humans are con- to C57BLi6 mice for three days R. D . IRONS to founded by concomitant exposure to resulted in a depression of a variety vs other solvents. Occupational exposure of functional immune parameters Department of Pathology, $Q benzene has l o w been a s s o c u ranging from decreased plaque form- Chemical Injustry Institute Qf 3. with bone marrow depression and an ing-cell response to a loss of spleen id increased incidence of blood dvscr- cellularity.'' Tice er al." observed a Jf -Je r. including leukopenia. lymphocytopenia, Virombocytopenia. pancyto- significant increase in the frequency Research Triangle Park. of sister chromatid exchanges in bone h;;: Carolina 2 t 9 , penia, leukemia and lymphoma.' marrow cells of CBA/2 mice follow- '. Lymphocytopenia has frequently been ing exposure to 3100 ppm benzene for PLAINTIFFS IC observed in individuals chronically 4 h. Bone marrow cell proliferation EXHIBIT 3 exposed to benzene, and alterations in was inhibited, but no increase in the immune parameters have been frequency of chromosomal aberra- L i. reported along with benzene-induced tions was observed. References IS l y m p h o c y t ~ p e n i a . ~T' h~e' ~association Benzene does not appear to be S of leukemia or lymphoma with directly myelotoxic. but must be 1. For an extensive review of benzene S. chronic benzene exposure is docu- metabolized to form proximate toxic toxicity, see S. Laskin and B. D. mented by numerous case reports and species. Benzene is oxidized via the Goldstein. Benzene toxicity - a critical )- d k retrospective studies.' Although the incidence of leukeniia varies significantly among various studies. it is not strikingly high. Aksoy er (11.' reported mixed function oxidase system in liver with the formation of potentially reactive intermediates. However, toxicity does not appear to be evaluation. J. Toxicol. E'nviron. Health Supplement 2 (1977). 2. L. J. Goldwater, Disturbances in the blood following exposure t o benzol. J. Lab. Ctin. Med. 2 6 . 957-973 (1941). .in increased incidence of acute Jssociated with cytochrome PA50 3. A. Lange, R. Smolik, W. Zatonski and myelogenous leukemia in Turkish enzyme activity, but rather with J. Szymanska, Serum immunoglobin shoe workers chronically exposed to osidation and conjugation pathways levels in workers exposed t o benzene, benzene. The annual incidence of that presumably give rise to phenol toluene and xylene. lnt. Arch. leukemia was 13 per 100000, coni- and the poIy hyd roxy late d me tab o lit es Arbeirsmed. 31,45-50 (1973). pared with 6 per 100000 in the general population. Alternatively. JIcMichael er aL6 reported a twofold increase in the incidence of lymphatic leukemia in rubber workers chroni- of Rickert et d Z 0and Greenlee et uLzl demonstrated a relationship between benzene-induced lyniphotoxicity in rats and the concentration of the principal dihydroxy- 4. N. V . Revnova, Concerning autoimmunity shifts in chronic occupational benzol poisoning. Gig. Tr. Prof. Zabol. 7,38-41 (1962). 5. M. Aksoy, S. Erdem and G. Dincol, Leukemia in shoe-workers exposed cally esposetl to benzene. Other metabolites. hydroquinone and chronically t o benzene. Blood 44, studies have found increased inci- catechol, accumulating in target 837-841 (1974). dence of Hodgkin's lyniphoma7 and tissues. Moreover, rccen t studies 6. A. J. McMichael, R. Spirtas, L. L. erythroleukemia8 in individuals with J history of chronic benzene exposure. Chronic toxicity: There is at present no convincing animal model for leukemia associated with benzene ex- indicate that short-term intravenous or intraperitoneal administration of hydroquinone or catechol to C57BLi6 mice results in lymphocytopenia and suppression of a variety of immune Kupper and J. F . Gamble, Solvent exposure and leukemia among rubber workers: A n epidemiologic study. J. Occup. Med. 17,234-239 (1975). 7. M. Aksoy, S. Erdem, K. Dincol, T. Hepyuksel and G. Dincol, Chronic posure. despite several attempts functional responses similar to those exposure to benzene as a possible reported in the literature. This is Jue. in part, t o a low incidence of '*cncountered following benzene adniini- s t ra t ion . contributory etiologic factor in Hodgkin's disease. Blur 2 8 , 293-298 leukemia JS well as a lack of coniistency J i n o n g various studies. Ward L'r d 9observed no statistically signifi-i a n t increase in leukemia in male C57BLi6 mice administered a variety of subcutaneous doses o f benzene h i Y$Y(J studies: Morimoto ~ n d W O I ~ ~ol"x~erved ;in increase in the frequency of sister chromatid e s changes in human lymphocytes exposed t o hydroquinone or catechol in culture. and 7rtinek c f ( I / . (1974). 8. B. Galavotti and F. M.Troisi, Erythro- leukemic myelosis in benzene poisoning. Br. J. lndust. Med. 7. 79-81 ( 1950). 9. J. M. Ward, J. H. Weisburger, R . S. Yamamoto, T . Benjamin, C. A. Brown f o r 5-1 weeks. S n y d c r ('r :I/. I" reporteci identified til iiroquinonc :IS t h e and E, K . Weisburger, Long term effect .in incidence for myelogenous principal iiict;il>olic intc.rnii.iliatc re- of txnzene in C57BL/6 mice. Arch. le1lketni:i L > f Y-!O in C'D-1 mic: .;ponsil~l; I'i)i-t h c covalent hind in^ t i l Environ. Healrh 30, 22- 25 119751 J O I I R N A L O F A P P L I E D T O X I C O L O G Y , V O L 2 PI0 1, 1922 57 10. C. A. Snyder, E . D. Goldstein, A . R. Sellakumar, R. E. Albert and S. Laskin, The toxicity of inhaled benzene. Toxicol. Appl. Pharrnacol. 45, 265 Abstract (1978). 11. C. Maltoni and C. Scarnato, First experimental demonstration of the carcinogenic effects of benzene. Med. Lavora 5, 352-357 (1979). 12. C. A. Nau, J. Neal and M. Thornton, C,-C,, fractions obtained from petroleum distillates, Arch. Environ. Health 12,382-393 119661. 13. R. D. Irons, H. d'A. Heck, 6. J. Moore and K . A. Muirhead, Effects of shortterm benzene administration on bone marrow cell cycle kinetics in the rat. Toxicol. Appl. Pharmacol. 51, 399409 (1979). 14. R. D.Irons and 6. J. Moore, Effect of short-term benzene administration on circulating lymphocyte subpopulations in the rabbit. Res. Comm. Chern. Pathol. Pharrnacol. 27, 147-155 (1980). 15. D. Wierda, W. F. Greenlee and R. D. Irons, Immunotoxicity of benzene metabolites in C57BL/6 mice. Toxicol. Appl. Pharrnacol. 60, 410-417 (1981). 16. R . R. Tice, D. L. Costa and R. T. Drew, Cytogenic effects of inhaled benzene in murine bone marrow: Induction of sister chromatid exchanges, chromosomal aberrations and cellular proliferation inhibition in DBA/2 mice. Proc. Natl Acad. Sei. USA 77,2148-2152 (1980). 17. R. Snyder and J. L. Kocsis, Current concepts of chronic benzene toxicity. CRC Crit. Rev. Toxicol. 3, 265-288 119751. 18. W. F. Greenlee and R. D. Irons, Modulation of benzeneinduced lymphocytopenia in the rat by 2,4,5,2',4',5'-hexachlorobiphenyl and 3,4,3',4'-tetrachlorobiphenyl. Chem. Biol. Interact. 33, 345-360 (1981). 19. R. D. Irons. W. F. Greenlee, D. Wierda and J . S. Bus, Relationship between benzene metabolism and toxicity: a proposed mechanism for the formation of reactive intermediates from polyphenol metabolites in Biological Reactive Intermediates I 1 (ed. by R. Snyder. D. V. Parke, J. J. Kocsis, G. G. Gibson and D. A. Jollow) Plenum Press, New York (1981) in press. . 20. 0.E. Rickert. T. S. Baker, J. S. Bus, C. S. Barrow and R. D. Irons, Benzene disposition in the rat after exposure by inhalation. Toxicol. Appl. PharmaCO/. 49,417-423 (1979). 21. W. F. Greenlee, E. A. Gross and R. D. Irons, Relationship between benzene toxicity and the disposition of '"C labelled benzene metabolites in the rat. Chem. Biol. Interact. 33, 285-299 (1981). 22. D. Wierda and R. D. Irons, Hydro- quinone and catechol reduce the frequency of progenitor E-lymphocytes in mouse spleen and bone marrow. lrnmunopharrnacology in press. 23. K. Morimoto and S. Wolff. Increase of sister chromatid exchanges and perturbations of cell division kinetics in human lymphocytes by benzene metabolites. Cancer Res. 40, 11891193 11980). 24. A. Tunek, K. L. Platt, M. Przybylski and F. Oesch, Multistep metabolic activation of benzene. Effect of superoxide dismutase on covalent binding t o microsomal molecules and ider.tification of glutathione conjugates using high pressure liquid chromatography and field desorption mass spectrometry. Chern. Biol. Interacr. 33, 1-17 (1980). 25. R. W. Pfeifer and R. D.Irons, Inhibition of lectin stimulated lymphocyte agglutination and mitogenesis by hydroquinone: Reactivity with intracellular sulfhydryl groups. Exp. Mol. Pathol. 35, 189-198 (1981). 26. R. D. Irons and D. A. Neptun, Effects of the principal hydroxy-metabolites of benzene on microtubule polymerization. Arch. Toxicol. 45, 297-305 (1980). 27. R. D. Irons, D. A. Neptun and R. W. Pfeifer, Inhibition of lymphocyte transformation and microtubule assembly by quinone metabolites of benzene: Evidence for a common mechanism. J. ReticuIoendorheL Soc. 30,359-372 (1981). 0 Heyden & Son Ltd, 1982 c. MO The Ter: Else 198 duc ge* we1 illu: disc cha disc ,hi the age sho anc for res of the to of altl Pla bil co1 59 .IIlrlRNAL O F APPLIED TOXICOLOGY,VOL. 2 , N o . 1, 1982 0 Heyden 6; Son Ltd, 1982 c