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Toxicokinetic behaviour of some pure substances present in these streams has been extensively studied and reported. In many circumstances the body burden of the substance and/or metabolites is dependent upon several factors such as the rate and extent of uptake, distribution, metabolism and excretion. In complex mixtures, however, the toxicokinetics of even well-studied pure substances may vary depending upon interaction with other chemical species available within the mixture. For example, the substances present may compete for the uptake, metabolism, and/or elimination of the complex mixture. This situation, already complicated, is further exacerbated when the composition of the mixture is uncertain and variable.

For this ‘Resin Oils and Cyclic Dienes’ category the marker substances (benzene, 1,3-butadiene, isoprene, toluene, naphthalene, styrene and C8 aromatics), in their pure form, have well-defined toxicokinetic parameters that have been taken into account during the derivation of their respective DNEL’s. The overall DNEL of this category is driven by the DNELs for benzene, naphthalene and styrene and already incorporates critical information on the toxicokinetic behaviour of these substances, albeit in a pure state.

The toxicokinetics of benzene has been extensively studied and was recently reviewed by ATSDR (ATSDR, 2007a). ATSDR concluded "Inhalation exposure is probably the major route of human exposure to benzene, although oral and dermal exposures are also important. Benzene is readily absorbed following inhalation or oral exposure. Although benzene is also readily absorbed from the skin, a significant amount of a dermal application evaporates from the skin surface. Absorbed benzene is rapidly distributed throughout the body and tends to accumulate in fatty tissues. The liver serves an important function in benzene metabolism, which results in the production of several reactive metabolites. Although it is widely accepted that benzene toxicity is dependent upon metabolism, no single benzene metabolite has been found to be the major source of benzene hematopoietic and leukaemogenic effects. At low exposure levels, benzene is rapidly metabolized and excreted predominantly as conjugated urinary metabolites. At higher exposure levels, metabolic pathways appear to become saturated and a large portion of an absorbed dose of benzene is excreted as parent compound in exhaled air. Benzene metabolism appears to be qualitatively similar among humans and various laboratory animal species. However, there are quantitative differences in the relative amounts of benzene metabolites”. The present analysis confirms the ATSDR statement. More specifically, human inhalation exposure is estimated to be approximately 50%, oral exposure assumed to be 100% (this value used for DN(M) EL calculations). Percutaneous absorption is estimated at 0.1% (Modjtahedi and Maibach, 2008) whereas a QSAR model determined a maximum value of 1.5% (Ten Berge, 2009). For percutaneous absorption of benzene from petroleum streams a value of 1% is considered appropriate. This value is based on experiments with compromised skin and with repeated exposure (Blank and McAuliffe, 1985; Maibach and Anjo, 1981) as well as the general observation that vehicle effects may alter the dermal penetration of aromatic compounds through skin (Tsuruta, et al, 1996).

ATSDR have also reviewed the toxicokinetics of naphthalene (ATSDR, 2005) and report that naphthalene is readily absorbed into the systemic circulation following inhalation or ingestion. Systemic absorption of naphthalene can also occur following dermal contact however, the rate and extent of naphthalene absorption for all routes is unknown in many instances. Naphthalene is initially metabolised into a number of reactive epoxide and quinone metabolites by cytochrome P450 oxidation. Metabolites of naphthalene are excreted in the urine as mercapturic acids, methylthio derivatives and glucuronide conjugates. Glutathione and cysteine conjugates are excreted in the bile. Following ingestion the urinary excretion of naphthalene metabolites is prolonged due to delayed absorption from the gastrointestinal tract.

Styrene toxicokinetics were reviewed by ATSDR in 2007. It can be concluded that styrene is well absorbed by the inhalation and oral routes and poorly absorbed through the skin. Once absorbed, styrene is widely distributed throughout the body, with the highest levels detected in fat. There are several metabolic pathways for styrene; the primary pathway is oxidation of the side chain by cytochrome P450 to form styrene 7,8-oxide. The styrene oxide is further metabolized to ultimately form mandelic acid or phenylglyoxylic acid or can be conjugated with glutathione. Styrene is rapidly eliminated primarily in the urine as mandelic acid and phenylglyoxylic acid.

The EU Risk Assessment Report (EU, 2002) contains a comprehensive review of the toxicokinetic information on 1,3-butadiene. In summary, various animal studies have shown rapid absorption of 1,3-butadiene by the lungs. In rodents, uptake and metabolism obeys simple first order kinetics at concentrations up to about 1,500 ppm, above which saturation of the process appears to occur. There are no data on the toxicokinetics of 1,3-butadiene following oral or dermal exposure, and their contribution to uptake and metabolism of 1,3-butadiene is anticipated to be negligible. After inhalation exposure both rats and mice show high concentration of 1,3-butadiene and its metabolites in their body tissues. The highest concentration are observed in the fat with lower levels in the blood, heart, lung, liver, bone marrow, thymus and kidney, with levels consistently higher in the target tissues of mice than rats. Available data indicate that metabolism is qualitatively similar among the various species (including humans) studied, although there may be quantitative differences in the metabolic rates and the proportion of metabolites generated. The major metabolic pathway involves initial oxidation of 1,3-butadiene via cytochrome P-450 enzymes (predominantly P-450 2E1, although other isozymes may also be involved) to the reactive metabolite, 1,3-butadiene monoxide (or epoxybutene). Epoxybutene can be further activated via cytochrome P-450 mediated transformation to another active metabolite 1,2,3,4-diepoxide (or diepoxybutane). The epoxybutene and diepoxybutane can be detoxified by hydrolysis or glutathione conjugation and is mediated by epoxide hydrolase and glutathione S-transferase. Epoxybutene, diepoxybutane and crotonaldehyde are all DNA-reactive and known mutagens and are believed to be responsible for the toxic effects of butadiene. Extensive data indicate that the active epoxide metabolites (including diepoxide) are formed to a greater degree in mice than in rats exposed similarly to 1,3-butadiene. A comparison of butadiene epoxide levels in target tissues (blood, bone marrow, lung, heart, fat, spleen and thymus) of rats and mice following low level exposure to 1,3-butadiene showed consistently higher epoxide levels in mouse than in rat tissues. The greater susceptibility of mice to the toxic effects of 1,3-butadiene may be related to the higher rate of formation of epoxybutene and limited detoxification, resulting in greater accumulation of the active metabolites in this species. 1,3-butadiene is excreted via the respiratory tract, urine or faeces. In rodents, urinary excretion takes place in two phases with 77-99% of the inhaled dose excreted with a half-life of a few hours, while the remainder is excreted with a half-life of several days. There is no evidence for bioaccumulation of 1,3-butadiene.

Isoprene is formed endogenously in humans; the sources proposed include mevalonic acid via the intermediate product dimethylallyl pyrophosphate (precursors of cholesterol), the peroxidation of squalene and from the decomposition of farnesyl (3 isoprene units) or geranylgeranyl residue (4 isoprene units) of prenylated proteins. Isoprene exhibits saturation kinetics in rats and mice For humans at low concentrations, the rate of isoprene metabolism to its epoxide metabolites is about 8-14 times lower than in rodents. The rate of metabolism was directly proportional to the exposure concentration at concentrations up to 300 ppm. Saturation of isoprene metabolism was nearly complete at about 1000 ppm in rats and at about 2000 ppm in mice. The maximal metabolic elimination rate in mice was determined to be at least 400µmol/hr/kg, which is about three times faster than that found in rats (130µmol/hr/kg). The whole body half-life of isoprene was 6.8 minutes in rats and 4.4 minutes in mice. The internal dose of isoprene was found to be greater in mice than rats after exposure to the same concentration. At concentrations above 1000 ppm, mice absorb three times more isoprene per kg body weight compared to rats, though at lower concentrations, the species difference in uptake became smaller (approx. two-fold at 700 ppm). Metabolites of isoprene were detected in the blood, nose, lungs, liver, kidneys, and fat of male F344/N rats exposed to 1,480 ppm [14C]-labelled isoprene. In liver microsomes, isoprene is metabolized by cytochrome P450 oxidation to the monoepoxide metabolites, 3,4-epoxy-3-methyl-butene and 3,4 -epoxy-2-methyl-butene. Both monoepoxides can be further metabolized to the diepoxide metabolite, 1,2:3,4-diepoxy-2-methyl-butane. The epoxides can also be hydrolysed or can be conjugated with glutathione. It is also expected that epoxide diols can be formed. A physiologically-based toxicokinetic (PT)-model has been constructed and used to simulate the inhalation of isoprene, its distribution by the blood flow, its metabolism, endogenous production, and exhalation as unchanged isoprene (Filser et al, 1996; Csanady and Filser, 2001). The model compartments consist of air, lung, richly perfused tissues, fat, muscle, and liver. Mouse, rat and human partition coefficients were determined experimentally. The endogenous production of isoprene was considered to occur only in the human liver and was described by zero-order kinetics. Taking into account species-specific partition coefficients and physiological processes (ventilation or blood flow), pulmonary uptake, accumulation in the blood and tissues, exhalation and rates of isoprene metabolism were comparable in rodents and humans. The PT model predicted that for exposure concentrations up to 50 ppm, the rate of isoprene metabolism are about 14 times faster in mice and about 8 times faster in rats than in humans. At 0 ppm atmospheric isoprene, the rate of metabolism in humans is 0.31 μmol/hr/kg body weight and represents the part of endogenously produced isoprene that is metabolized. About 90% of the endogenously produced isoprene is metabolized, and only about 10% is exhaled unchanged. Because of the rapid isoprene metabolism, Csanady and Filser (2001) concluded that isoprene cannot accumulate in humans at low exposure concentrations. Dermal absorption is low, with model prediction giving absorption of approximately 0.3%

Toluene toxicokinetics were reviewed by the EU (EU, 2003a). In summary, the major uptake of toluene vapour is through the respiratory system. It is absorbed rapidly via inhalation and the amount absorbed (approximately 50%) depends on pulmonary ventilation. Toluene is almost completely absorbed from the gastrointestinal tract. Liquid toluene can be absorbed through the skin but dermal absorption from toluene vapours is not likely to be an important route of exposure. Dermal absorption of liquid toluene was predicted using a model which considers absorption as a two stage process, permeation of the stratum corneum followed by transfer from the stratum corneum to the epidermis. The model predicted a maximum flux of 0.0000581 mg/cm2/min giving a dermal absorption value of approximately 3.6% of the amount applied as liquid toluene. Toluene is distributed to various tissues, the amount depending on the tissue/blood partition coefficient, the duration and level of exposure, and the rate of elimination. Biotransformation of toluene occurs mainly by oxidation. The endoplasmic reticulum of liver parenchymal cells is the principal site of oxidation which involves the P450 system. Analysis of blood and urine samples from workers and volunteers exposed to toluene via inhalation in concentrations ranging from 100 to 600 ppm (377-2,261 mg/m3) indicate that of the biotransformed toluene, ~ 99% is oxidised via benzyl alcohol and benzaldehyde to benzoic acid. The remaining 1% is oxidised in the aromatic ring, forming ortho-, meta- and para-cresol. In the rat, elimination of toluene is rapid with most toluene eliminated from fat after 12 hours. Within a few hours after termination of exposure the blood and alveolar air contains very little toluene. A proportion (around 20%) of the absorbed toluene is eliminated in the expired air. The remaining 80% of the absorbed toluene is metabolised in the liver by the P450 system, mainly via benzyl alcohol and benzaldehyde to benzoic acid. Benzoic acid is conjugated with glycine and excreted in the urine as hippuric acid.

The metabolism and kinetics of xylene isomers has been reviewed extensively by ATSDR (2007c). All the xylene isomers are well absorbed via the oral route. They are rapidly distributed through the body and any unmetabolised compound quickly eliminated in exhaled air. In gavage dosing experiments in animals, 90% absorption has been estimated. In humans, inhalation absorption has been estimated at about 60-65% based on human data. The major pathway of xylene metabolism in humans involves mixed function oxidases in the liver, with minor metabolism occurring in the lung and kidneys. Xylenes are transformed primarily to methylbenzoic acid followed by conjugation with glycine to form the main metabolites, the corresponding methylhippuric acid isomers, which are eliminated in the urine.



ATSDR (2005). Toxicological profile for naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. U.S. Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry.

ATSDR (2007a). Toxicological profile for benzene. U. S. Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry.

ATSDR (2007b). Draft toxicological profile for styrene. U. S. Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry.

ATSDR (2007c). Toxicological profile for xylene. U. S. Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry.

Csanady GA and Filser JG (2001). Toxicokinetics of inhaled and endogenous isoprene in mice, rats and humans. Chem.-Biol. Interact., 135-136, 679-685.

EU (2003a). European Union Risk Assessment Report for Toluene. EC Joint Research Centre http: //ecb. jrc. ec. europa. eu/DOCUMENTS/Existing- Chemicals/RISK_ASSESSMENT/REPORT/toluenereport032. pdf

Filser JG, Csanady GA, Denk B, Hartmann M, Kauffmann A, Kessler W, Kreuzer PE, Putz C, Shen JH and Stei P (1996). Toxicokinetics of isoprene in rodents and humans. Toxicology, 113, 278-287.