Document nm5zjNDdd06Ko9Kym4nQK27R8

BENZENE AND NON-HODGKIN'S LYMPHOM SIMON R. O'CONNOR'*, PETER B. FARMJX2 A N D IAN LAUDER3 'Department of Histopathology, Leicester Royal Infirmary NHS Trust, Leicester, U.K 2BiomonitoringSection, MRC Toxicology Unit, University of Leicester. Leicester, U.K -'Departmentof Pathology, University of Leicester, Leicester, U.X SUMMARY Incidence rates for non-Hodgkin's lymphoma (NHL) have been rising throughout the world for several decades, and no explanation exists for the majority of this increase. The commonest subtypes of NHL have no lymphoma development has been linked with exposure to a variety of chemicals, including nitrates Benzene, a solventand important constituent of petrochemicalproducts, is a potent lymphomageni exposure in humans is associated with both acute myeloid leukaemia and NHL.. Much current environmental benzene exposure in the general public may underlie a proportion of the increase exposure in the environment is derived from vehicle exhaust emissions, whose increase has disease. Mathematical modelling has been used to calculate an acceptableconcentration of from industrial exposure, but the recommended target concentration in the U.K. of 1p Detailed investigation of the health effects of low-level benzene exposure awaits an accurate assay for quantifying long exposure. The 32p post-labelling technique for the detection of toxin-specific DXA adducts is extremely sensitive and has been a*lid in the biomonitoring of expasure to a number of carcinogens, but benzeneDX4 adducts have to date proved elusive of d Copyright 01999 John Wley & Sons, Ltd. KEY WORDS-benzene; non-Hodgkia's lymphoma; aetiology OITRODUCTION Until recently regarded as a rare malignancy, nonHodgkin's lymphoma (MIL), including multiple myeloma, has steadily risen in incidence over the last four decades to become the ei&th commonest cancer in the U.K.' and sixth commonest in the U.S.* The increase in its frequency is of particular significancesince its occurrence over a wide age range results in a disproportionately high number of years of life lost relative to most other forms of malignancy. This increase has been estimated to be of the order of 3-5per cent between 1973 and 1990 in the U.S., compared with an overall increase in cancer at all sites of 1-2per cent during that period, and has continued between 1990 and 1995 when a decrease in overall cancer incidence was recorded.* A comparable upward trend has been observed in the U.K. and also, with remarkable uniformity, in almost all countries of both the industrialized and the developing world where tumour registries are maintai~~eAd.ll~age groups, both sexes, and all racial categories have shown a rise in cases of the d i s e a ~ ea,n~d the rate of increase in the U.S. has been exceeded amongst malignancies only by lung cancer in women and malignant melanoma in both sexes. The advent of AIDS, more widespread use of iatrogenic immunosuppression, and the application of more accurate molecular diagnostic techniques can explain a proportion of this increase, but the large *Correspondence to: Dr S.OConnor, Department of Histopathology, Leicester Royal Infirmary NHS Trust, Leicester, LE1 5 \ W , U.K. CCC 0022-3417/99/13OU!%06S I 7.50 Copyright 0 1999 John I W e y S: Sons, Ltd. AETIOLOGY OF NOS-HODGMS'S LYMPH The search for possible aetiologkal factors group of related but diverse clinicopathological which show few predilections for any particular or social group, has been no more than a partial SUF to date.7 Congenital and acquired immun states are perhaps the best recognized risk lymphoma development.* Autoimmune disea disposing factors for marginal zone B-cell several extranodal sites? and the associ gastric marginal zone 1)mphoma and infection is well known. lo Herpwiruses, n Epstein-Barr virus (EBV). and the human lymphomalleukaemia retrovirus11-'3are also causes of several relatively rare categories of commonest subtypes and the vast majority remain, however, of unknom aetiology. While there continues to be no lack of theories. ranging from excessive exposure t to the effects of electromagnetic fields.l5-l6 increasindy being focused on the chemical toxins in causing this g o u list of suspect compounds includes t of herbicide^'^.'^ especially the t\ dichlorophenoxyacetic acid. and pesticides which the organochlorines (including I '. fsphates (malathion) ar-atal Contami- `ground and surface wszz & nitrates from is not uncommon m Ist awntryside, and velopment of 1~mphon;s-ilik e n shown to bositively with bels d in drinking 1 study in the Anxxiz mi%isr" Intensifi- farming in the psi b & d e s with greater `echemicals. is bclicxd underlie at least e increase in I~mpbcxm= ~ j i6n rural areas." in Sweden has idasti% signkmtly raised - ywof polghlorinared -5&ixn& (PCBs) in E from hXL iz - n with a and these r s i k Z b m confirmed ey at the S a t i O d &hxitute in the er study also dancxszxed a synergistic n elevated PCB !a&lslf rhc presence of in the causarjon d X i i 1 exposure to s=zi dwm.s has also with an incrraS, S s of developing .24 Associations ,.ldsr -3eaen risk of devel- of NHL and e m p l o : ~ki hairdre~sing'~ t'mlvents in hair dytj h . 2 -%en >u,ogested as a kB&or); the dry-cleaning k d z s r r : ~ ~hemical,'~ and styrenr") man- and amonzst knT,he solvents m k r m+n include styrene, kmthylene. and b e m e . Tz-=- the structural $pe of the organic aromari=k y k a r b on group of ids, is probabl: elicitingmzrz m m t interest as a ble environmental caw d lpphorna than any ::Substance. t ENZEhT--4 POSSIBLE CACSE OF LYI\IPHO_rL4 (C6H6) is a by-prodta dtk combustion of and is produced in forest fires and of hWL iri ?kiadustrial setting.3gEmploymeiit in the Fa- industry has been noted to carry an increased risk ot-I:mphoma,M and exposure to benzene in parockmid products may be reflected in the increased iiikknce observed amongst road transport worker$' aDd oil tanker crews.42Police motorcyclists in R o ~ r em~o~l pump attendants in ItalyY4 and automobik ns5anics in the U.S.?j have all been shown to e x h i i an excess of NHL cases, again strongly suggaTi\.c of a causative role for benzene as a major constituent aithin petroleum products and vehicle exhaust &sons. MecJirtnima of toxicity Be- is effectively absorbed via the lungs and about 50 pzr c n t of the inhaled dose is retained.46 It preferen- concentrates in tissues having a high fat content. d w to its lipid s0lubility,4~ especially the central nmous system and the bone marrow. Initial metabolism of benzene is to several ring-opened and h y d r o q b e d products, the most important of the latter being phaol, hydroquinone, and catechol, and is mzdiatzd b? hepatic microsomal cytochrome P-450 o x i h 93t.m~s.18.~9The bone marrow appears to be uniquel>-w t i b l e to benzene toxicity, due to a com- bination of its high fat content and the presence of high levels of the myeloperoxidase enzyme contained within its myeloid czIls.50 This enzyme is required for the further m b o l i s m of these compounds to the probable final toxic mztabolites, p-benzoquinone and its semi- quinone radical. Electrophilic free radicals are also produced as part of this reaction.jl Sigdcantly, the zymbal _gland of rodents, which is subject to benzene- induced &omas, also possesses a high content of both lipids and myeloper~xidase.~~ Acute highdose benzene toxicity is manifested by neurological symptoms including nausea and vertigo, progmshg to coma and death,53,54while at lower doses the most significant toxic effect is depression of bone marrow function, leading to pancytopenia or aplastic anaemk~~~T.5h6e latter effects are mediated partly by induction of apoptosis in haematopoietic cells,57 and also through effects on stromal macrophage func- t i o n s 3 Levels of prostaglandin E2 within bone marrow are increased by benzene, with a resultant down-regulation of haematop0iesis,~9a mechanism of toxicitv which has been effectively prevented by co-adr;linistration of indomethacin in The geno- toxic effects of benzene metabolites have been exten- sively documented in a variety of in vitro and in vivo studk%many of the latter utilizing colony-forming unit assays to detect effects on early stages of haemato- p~ksis.~M'uch of their toxicity stems from inhibition of the topoisomerase I1 enzyme, whose physiological fundion is to facilitate the relaxation of supercoiled DNA through the introduction and religation of double- stranded breaks in its structure.62~63This mechanism of toxicity is shared with certain chemotherapeutic drugs of the epipodophyllotoxin group, including etoposide and teniposide, and is responsible for the therapy-related leukaemia occasionally associated with their use@. ' It - .. I t .on. ~ A OA<, t+oao\ results in a clastogenic pattern of DNA damage, similar to that seen with ionizing radiation, with single and double strand breaks giving rise to deletions, translocations, and n o n - d i s j u n ~ t i o n s .B~e~n~ze~ne is also believed to damage histone proteins, thus secondarily contributing to DNA strand breaks through alterations in DNA folding.48 Cytogenetic alterations and benzene exposure A non-random pattern of karyotypic abnormalities has been shown in a study of benzene-exposed workers, with chromosomes 2, 4, and 7 most frequently affected,66and the search for possible proto-oncogenes and tumour suppressor genes at these sites continues. There are indications that 7q may harbour a tumour suppressor gene whose loss is important in AML,67,68 and other current work suggests that benzene-exposed workers have an increased rate of translocations between chromosomes 8 and 21,69t(8,21) being the most common translocation found in AML.70 Although the clastogenic pattern of DNA abnormalities is highly conducive to producing translocations, as seen in several types of lymphoma, those specifically associated with NHL have not been demonstrated to date. Benzene also appears to exert significant epigenetic effects which lead to dysregulation of normal cellular pathways of growth and differentation. It is believed to up-regulate expression of the early growth-associated genesfos and jun,7' and to produce elevated levels of tumour necrosis factora.72 Hydroquinone has recently been shown to inhibit the action of the CPP32 protease,73 an interleukin-1B converting enzyme which acts as a late effector in the apoptotic cascade. The combined effect of this inhibition of apoptosis and genotoxicity may lead to aberrant haemopoiesis and provide a fertile soil for neoplastic transformation. Exposure to benzene in rhe environment About 70 per cent of benzene present in the environment is derived from motor vehicles,74the vast majority in the form of exhaust emissions, where benzene is present as a volatile by-product of the combustion of petrol and diesel fuels. Smaller amounts are also lost into the atmosphere during petrol tank filling and as evaporative losses from the tank with engine temperature changes. The majority of benzene exposure in non-smokers results from respiration of these emissions, with small amounts also possibly being taken in from household sources as above. The quantity of benzene introduced into the atmosphere has steadily increased since the 1950s in line with the increasing numbers of vehicles on the roads, but has fallen over the past decade in the U.K. due to new legislative controls on vehicle emissions. Current annual emissions from all sources amounted to approximately 35 kilotonnes in 1995.75 While environmental benzene levels have not been measured over much of the Third World, many cities in these countries suffer from particularly Severe air pollution, exacerbated by the widespread use of inefficient two-stroke en$nes and the rarity of catalytic Cop!right D 1999 Juhn \V~lc>d: k o Li~d converters, and benzene concentrations are like correspondingly high. Once present in the atmosphere, benzene mo tend to last for about 9 days on and can be distributed over wide areas by wind before undergoing photodegradation. A recommended running annua, mean level of 5 parts per billion (ppb) and a recorn- mended target concentration of 1 ppb have been set by the National Expert Panel on Air Quality Standards (EPAQS)."P~~This quantitative risk assessment derives largely from mathematical modelling studies based on current knowledge of the risks of industrial exposure Benzene levels in the U.K. are measured at 12 automatic monitoring centres by the Department of the Environment, 11 situated in urban centres and one at a rural site. Average concentrations in 1995 raged between 0 7 and 2.5 ppb in urban locations, with rural levels being on average 30-35 per cent of those in cities.79 Mean benzene levels of up to 37 ppb were reported at some roadside monitoring sites and,pak concentrations reached 43 ppb in Middlesbrough, where the presence of several petrochemical plants is believed to contribute to higher than average values. Although in-car values are not routinely monitored, the largest study to date of motorists has shoun them to be exposed to levels of benzene of the order of three to four.thes those received by pedestrians for a given ambient concentration.80 In 1995, the EPAQS recommended running annual mean level was not exceeded at any site, although the recommended target concentration was exceeded at all urban sites except Average indoor benzene Ielels in the U.K. have recently been estimated during a study in the Avon area by the Building Research Establishment.81It was found that indoor concentrations averaged 1-1-6 times those outdoors. Urban homes showd significantly higher levels. and in 5 per cent of homes surveyed, the recom mended running annual mean concentration of Sppb was exceeded in at least one room. Homes having an attached garage had higher than average levels,' and when a a r was kept in the g a m s this resulted in an 80 per cent increase in benzene concentration within the home, probably due mainly to evaporation of petrol from the fuel tank. Smokingb\- the significantly increased The issue of exposu filling has been examined i where personal sa tor e x p s i r e of petr refuelling. mean benzene though thz procedure lasted onlx exposure could be expected to k received by motorist in the U.K., wh self-senk. although there are .- -. -%--. ..-- I- __- BIORlONITORING OF BENZENE EXPOSURE c !argest \posed times nbient ,ended iy site. n was have n area found , those higher .ecorn5 PPb ing an S , and I in an liin the petrol I led to 31 tank 1 Italy. moniDuring pb, 81Similar private '11s arc !ion 10 petrol drati1.C heW itely 10 ,.ations l.e *:..a recently been described for the measurement of urinary the industrial setting to benzene metabolite^,^^^,^^ but an effective means of e possible risks of environmental benzene estimating long-term exposure is still awaited. It is likely he non-occupationally exposed public is that this will focus on the measurement of adduct 1, but is unavoidable in compounds formed by covalent bonding between DNA formation on exposure and benzene metabolites as part of the process of genetic damage by the Adducts of unique structure are formed by many carcinogens in interaction with s of as low as 40ppb DNA and their levels within tissues reflect a combina- d to increased chromosomal aberrations in tion of a subject's exposure and the subject's metabolic es,92 but organic hydrocarbons frequently capacity to generate the genotoxic metabolites.lo* They variation in toxicity between species. Poten- are believed to undergo repair with time, leading to a the differences in gradual diminution in their number, the rate being r many industrial dependent on the nature of the carcinogen and its site of with the continu- adduct formation within DNA. Their measurement has been used as a 'molecular dosimeter' of exposure to a number of toxic chemicals.'mJ1oThe 32Ppost-labelling w that they may technique is currently the most sensitive method for the detection of adducts formed by carcinogenic com- pounds." This procedure involves an initial enzymatic digestion of the target DNA to be analysed for the presence of adducts down to its constituent nucleotides. omplicating factor is that vehicle exhaust This is followed by a second digestion step which a complex mixture of numerous organic dephosphorylates normal DNA nucleotides to nucleo- IUC chemicals and particulate matter, many sides. This conversion does not take place in adducted ia different mechani~rns.~~ nucleotides, due to steric hindrance by the attached hur dioxide, polycyclic carcinogen moiety, thus enabling their isolation. 32P- hydrocarbons (PAHs), PCBs, dioxins, labelled ATP is then added and the phosphate radio- and diesel exhaust particulates. As noted isotope is incorporated into the adducted nucleotides. ces have been themselves These can then be separated either by thin-layer chroma- with the development of NHL, and tography or by high-pressure liquid chromatography, city with benzene is highly probable. quantified by radioactivity determination, and if neces- sary, the structure of the adduct may be analysed further by mass spectrometry. DNA adducts of several PAHs have been successfully demonstrated in exposed workers, but benzene adducts have so far proved extremely difficult to detect compared with those of most carcinogenic. co_mp.ound*s*," although some progress is -TGSWr .. 7?r In summary, there is compelling evidence to suggest a role for several atmospheric pollutants, the most important of which is benzene, in the genesis of non-Hodgkin's lymphoma. The rise in environmental levels of benzene and related toxic compounds produced by increasing numbers of motor vehicles has closely paralleled the marked increase in incidence of the disease since the Second World War, which has occurred in almost every country where tumour registries are kept. Further experimental work will be required to establish this association with more certainty. A demonstrable lymphomagenic effect by vehicle exhaust emission constitu- ents would add to the already considerable evidence of their role in the causation and exacerbation of asthma and cardiovascular disease, and underline the urgency of a global reduction in emissions. Current predictions are that new motor vehicle registrations are set to continue their upward trend over the next decade in the U.K.,77 but the strict application of new legislation on emission limits of engines and on the storage and transport of petrol holds out hope of offsetting some of the effects of the increase, at least in the short term. There are, however, no signs of the implementation of such regulation in the developing world and the current uncon- trolled proliferation of motor vehicles in the rapidly growing cities of South and South-East Asia, Latin America, and Africa bears serious implications for the health of a large fraction of the planet's population. rg. Fontana A, PiaroC. Masala G, Prastaro C. Vineis p. lymphomas and environmental measurements of phen4 ecological anal+ and casecontrol study. Arch Enpiron~H, 384-387. p.? 19. Brown LM. 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