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Kinetics and metabolism • • The primary route of entry is via inhalation. Dermal absorption is poor. Reactive metabolites such as benzene oxide have been implicated in the mechanism(s) of benzene toxicity.
Health effects of acute exposure • Acute exposure may resemble solvent intoxication, clinically manifest as drowsiness, dizziness, delirium, loss of consciousness, respiratory arrest and death.
Health effects of chronic exposure • • Two, well documented adverse health effects of chronic benzene exposure are anaemia and leukaemia. Benzene is a known human carcinogen and clastogen but is not considered to be a reproductive toxicant.
Prepared by R P Chilcott CHAPD HQ, HPA 2007 Version 2
It is mutagenic and a genotoxic carcinogen. dizziness. resulting from suppression of bone marrow tissue . The assumption is made that there is no threshold to such effects and that any exposure results in some increase in risk.BENZENE – TOXICOLOGICAL OVERVIEW Toxicological Overview Summary of Health Effects Acute exposure to relatively high concentrations of benzene (benzol) may result in CNS disturbances consistent with solvent exposure. tremor. with a substantial number of case reports and epidemiological studies providing evidence of a causal relationship between occupational (chronic) exposure and various types of leukaemia . respiratory arrest and death . albeit this may be very small. ataxia.. Benzene is a known human carcinogen. Toxicological overview: Page 2 of 14 . loss of consciousness. delirium. drowsiness. A characteristic effect of chronic benzene exposure is aplastic anaemia. It is currently hypothesised that the carcinogenic effects of benzene are predominantly mediated via metabolites such as benzene oxide . viz. headache.
respectively ([18. 16]. Systemic absorption of benzene after ingestion is likely to be high. susceptibility to benzene toxicity is augmented in human individuals and animals lacking NQ01 [21. Although the actual metabolite that is responsible for the carcinogenic effects of benzene has not been definitively identified . 22]. Legislation to decrease the benzene content of engine fuels to less than 1%  and the compulsory introduction of catalytic converters on vehicle exhausts have significantly reduced this source of pollution. especially when dissolved in water and case reports of poisoning indicate that benzene is extensively absorbed by the oral route . Absence of CYP2E1 leads to a reduction of the cytotoxic and genotoxic effects of benzene in transgenic mice . principally through the combustion of fuels for cooking and heating and the operation of garden appliances such as lawn mowers and patio heaters  . in 2004. road traffic vehicles have represented the major source of benzene in the UK and accounted for ~ 60% of total emissions in 1990 . However. However. 99. there is evidence that this is mediated by benzene oxide.9% of an applied dose may vaporise from the skin surface before being absorbed . The metabolism of benzene has been widely studied in human and animal models due to its putative role in carcinogenesis (metabolic activation) [15. excessive dermal contamination may make a substantial contribution to the daily intake and so skin contact with benzene should be avoided . 19] as reviewed by ). Domestic sources currently contribute the greatest proportion (33%) of benzene emissions. When applied as a discrete droplet. Toxicological overview: Page 3 of 14 . there are significant species-specific differences in the extent to which benzene is metabolised by each pathway .BENZENE – TOXICOLOGICAL OVERVIEW Kinetics and metabolism Benzene is well absorbed by inhalation : systemic absorption of benzene from the lungs is greatest over the first few minutes of exposure (70 – 80% of inhaled dose) and decreases thereafter to approximately 50% of the inhaled dose after one hour . the proportion of benzene metabolised by each pathway appears to be dose-dependent. road vehicles accounted for less than 20% of UK benzene emissions . Historically. Sources and route of human exposure Benzene is a ubiquitous air pollutant which can vary widely in concentration according to location (Figure 1). The metabolic pathways implicated in benzene toxicity are broadly comparable across species. with hydroquinone and phenyl conjugation pathways predominating at lower (<10ppm) and higher (>10ppm) concentrations. Conversely. Furthermore. a reactive metabolite of CYP2E1  which is sufficiently stable (t½ ~ 7 – 9 minutes) to ensure distribution throughout the body. Dermal absorption of benzene is generally considered to be poor. Two enzymes have been particularly implicated in the mechanism of benzene toxicity: cytochrome P450 2E1 (CYP2E1) and quinone oxidoreductase (NQ01).
“ppb” = parts per billion.1 73 92 400 Toxicological overview: Page 4 of 14 . For the majority of the population. Ambient air concentrations of benzene within dwellings tend to be around twice as high as comparable outdoor concentrations (Figure 1) and smoking indoors can make a significant contribution to the concentration of benzene . Source Diet Air Smoking Food Water Rural (non smoker) Urban (non-smoker) 20 cigarettes per day Total Benzene (µg day-1) 1. Table 1: Current estimated (average) daily intake of benzene in adults. Table 1). although contaminated groundwater may potentially represent a significant source of benzene exposure . 16 traffic 14 12 Benzene Concentration (ppb) 10 8 indoors 6 4 outdoors 2 0 rural urban rural NS urban NS urban S roadside in vehicle Contributions to the daily intake of benzene from food and water are relatively low (less than 1½ to 2% of total. smoking and propinquity to road traffic are the predominant factors affecting daily exposure (Table 1). “S” = smoker.5 < 0. data from . “NS” = non-smoker. data from .BENZENE – TOXICOLOGICAL OVERVIEW Figure 1: Approximate concentrations of benzene in ambient air.
acute lethal dose of benzene in humans is estimated to be 125 mg kg-1.000 Duration of exposure (min) 480 300 60 60 30 30 5-10 Effect(s) No observable effect Headache. Recovery from an acute exposure is dose-dependent. shallow and rapid pulse. Signs of intoxication following ingestion include staggered gait. weakness Symptoms of illness Serious symptoms Endurable Dangerous to life Fatal Inhalation The commonly quoted “lethal dose” of benzene (20. Fatal exposures have been associated with asphyxiation. Benzene is irritating to the nose and respiratory tract at “high” concentrations . Toxicological overview: Page 5 of 14 . Concentration ppm 25 50-150 500 1500 3000 7500 19000-20000 mg m-3 80 160-480 1. vomiting. characterised by euphoria. It has been observed that aspiration of benzene directly onto the lungs causes “immediate pulmonary oedema and haemorrhage at the site of contact with the pulmonary tissue” . Overt signs of exposure have previously been referred to as “benzol jag”. asphyxiation or respiratory or circulatory arrest. coma and death . Ingestion The single. nervous irritability and unsteadiness in gait persisting in severe cases for two to three weeks . unsteady gait and confusion . central nervous system depression. central nervous system depression and possibly cardiac arrhythmias . delirium. Death may be due to CNS depression. lassitude. pnuemonitis. respiratory arrest.000 ppm) is an estimate based on a review of a single case report following 5 – 10 minutes’ exposure . Table 2: Summary of acute benzene vapour toxicity .BENZENE – TOXICOLOGICAL OVERVIEW Health Effects of Acute / Single Exposure Human Data General toxicity Benzene is not generally regarded as an acutely toxic material and there are correspondingly few reports pertaining to the (human) health effects of a single exposure. In general.600 4.800-64.600 24.000 60. somnolence.800 9. acute exposure to concentrations of benzene in excess of 500 ppm may illicit signs and symptoms consistent with solvent intoxication (Table 2). equivalent to 10 ml per 70 kg man-1. with breathlessness.
Toxicological overview: Page 6 of 14 . vesiculation and dermatitis . transient injury to the epithelial cells .BENZENE – TOXICOLOGICAL OVERVIEW Dermal / ocular exposure Whilst benzene is poorly absorbed through the skin. erythema. Eye contamination with droplets of benzene may cause a moderate burning sensation with only slight. viz. prolonged or excessive contact may cause signs consistent with the defatting (delipidising) effects of organic solvents.. Benzene vapour may cause a smarting effect on the eyes at high concentrations. Delayed effects following an acute exposure Most cases of acute benzene intoxication resolve spontaneously or with supportive care in the absence of long-term sequelae .
Genotoxicity Benzene is a human clastogen : chronic exposure results in consistent structural and numerical chromosomal aberrations in lymphocytes and bone marrow cells which may be observed for at least five years after cessation of (occupational) exposure . with bone marrow depression leading to aplastic anaemia being the most common clinical manifestation (occurring in approximately 1% of individuals exposed to > 100 ppm benzene) [11. In addition to effects on the haematopoietic system. one study has suggested that chronic benzene exposure to less than 1 ppm may induce haematotoxic effects in such genetically susceptible populations. Indeed. 30]. immune dysfunction  and cancer . any exposure is associated with some increase in risk. pancytopenia and myelodysplastic syndrome . 26. Further. Although the actual metabolite that is responsible for the carcinogenic effects of benzene has not been definitively identified . However. Benzene is also established as being leukaemogenic in humans [3. although it was recognised that more data were required before any definite conclusions could be drawn .BENZENE – TOXICOLOGICAL OVERVIEW Health Effects of Chronic / Repeated Exposure Human Data General toxicity The adverse health effects of chronic benzene exposure have been extensively documented and primarily relate to impairment of the haemopoietic system [23-34]. although this may be very small . altered differentiation of early progenitor cells and depletion of the stem cell pool . an excess of CYP2E1 [46-48] or deficiency of quinone oxidoreductase (NQO)  may enhance benzene toxicity. 36. Other effects on the haemopoietic system include leukopenia. 32-38]. since benzene is a genotoxic carcinogen (see below) the assumption is made that there is no threshold for its effect. agranulocytosis. benzene exposures have been implicated in neurological disorders . Susceptibility to benzene toxicity has been related to genetic polymorphisms [40-45]. I. anaemia. Toxicological overview: Page 7 of 14 . induction of apoptosis. detailed information on the general toxicity of benzene can be obtained from a number of comprehensive reviews [11. Other factors that influence the toxicity of benzene include the systemic distribution rates of metabolites and consequent events within bone marrow tissue such as secondary metabolic activation. 54]. 39]. Exposures to 1 ppm benzene for 40 working years has been considered not to be associated with any increase in leukaemia or any other haematological abnormality [11.e. a metabolite of CYP2E1 which is sufficiently stable (t½ ~ 7 – 9 minutes) to ensure distribution throughout the body . For example. there is evidence that it is mediated by benzene oxide.
However. multiple myeloma 956 Leukaemia. WBC (white Toxicological overview: Page 8 of 14 . Study Type¶ “n” 44 63 94 1 6 1 28.500 Putative disease outcome Original Reference                 Leukaemia Leukaemia.460 Acute and chronic leukaemia 391 Leukaemia Leukaemia Reproductive and developmental toxicity Benzene diffuses across the placenta and is considered to be fetotoxic in the presence of maternal toxicity . leukaemia 28. malignant lymphoma Hodgkin’s disease Case Subacute granulocytic leukaemia Haemocytoblastic leukaemia Acute myelogenous leukaemia Aplastic anaemia. General toxicity Numerous repeated dose studies in animals have shown that benzene produces bone marrow depression leading to a range of haematological effects including reduction in haematocrit. Putative disease outcome = disease state associated/correlated with occupational benzene exposure. multiple myeloma. acute myelogenous leukaemia 3636 Leukaemia Epidemiology 259 Lymphatic and haemopoietic neoplasms 2013 Aplastic anaemia.BENZENE – TOXICOLOGICAL OVERVIEW Carcinogenicity Benzene is classified by the IARC as Group 1 human carcinogen  and its role as a leukaemogen has been clearly established through a number of epidemiological studies (Table 3). Animal Data Animal studies are largely in accordance with the known toxicity of benzene in humans. Data derived from IPCS . Table 3: Empirical summary of studies pertaining to chronic (occupational) benzene exposure and putative disease outcomes. the carcinogenic effects of benzene in animals is primarily associated with epithelial tissue rather than leukaemia . decreased haemoglobin and a reduction in RBC (red blood cell). acute leukaemia Myeloid and monocytic leukaemia Leukaemia. Benzene is not considered to be a teratogen and there is currently no evidence that it causes reproductive effects in humans .
Some adverse effects on the foetus (reduced birth weight and/or minor skeletal variants) were seen at relatively high exposure levels (~ 150 mg m-3 and above). in studies with transgenic mice (using lac1 as a reporter gene). None has detected any teratogenic potential even at exposure levels that produced some evidence of toxicity in the maternal animals. Genotoxicity Although assays for the ability of benzene to induce gene mutations in bacteria were negative. Carcinogenicity Benzene has been shown to produce several types of neoplasms in both rats and mice after either oral dosing or inhalation exposure. Benzene is clearly an in-vivo mutagen. Thus. benzene clearly has mutagenic potential. benzene has consistently given positive results from in-vitro assays for clastogenicity . These include various types of epithelial neoplasms and a few lymphomas and leukaemias . There is in-vivo evidence to demonstrate that benzene is both clastogenic and induces gene mutations in animals. Toxicological overview: Page 9 of 14 .BENZENE – TOXICOLOGICAL OVERVIEW blood cell) and platelet counts. Decreased proliferation of B and T lymphocytes and resistance to infection has also been demonstrated . benzene induced gene mutations in the lung and spleen . Some haematopoietic changes were observed in offspring from adults exposed to lower levels (16 mg m-3 and above) . For example. Reproductive Toxicity A number of studies have been carried out to investigate the effect of exposure to benzene during pregnancy.
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