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Yamanashi Med. J. 6(8), 127"v135, 1991

Biological Monitoring of Exposure to Organic Solvent Vapors

I. A Physiological Simulation Model of m-Xylene

Pharmacokinetics in Man

Takashi KANEKo, Kazushi ENDoH,and Akio SATo

Dopartment ofEnvironmentalHealth, Medical Universidy ofYamanashi, Tamaho, Ya7nanashi 409-38,laPan

Abstract: A physiological pharmacokinetic model of the transfer of organic solvents in the

human body was developed. The model was comprised of seven compartments, i.e., lungs, vessel-rich tissues, vessel-poor tissues, muscles, fat tissues, gastrointestinal tissues, and liver, each

being connected to the others by blood fiow. The transfer of organic solvents was expressed by simultaneous differential equations, which were then solved numerically by a personal computer using a simple spreadsheet program. m-Xylene was used as the repi'esentative organic solvent. ・ .Partition coefficients of m-xylene betweeii blood and air and between body tissue and blood were experimentally determined with blood and tissues of rats. The metabelic constants (Vmax and Km) of m-xylene metabolism and the excretion rate constant of m-methyl hippuric acid (m-MHA) were also determined using rats. These animal data "rere scaled up and used as the simulation

parameters for humans. The results of the simulation of human exposure to m-xylene were '. essentially in agreement with human experimental data.

Key words: Physiologically based pharmacokinetic model, m-Xylene, m-Methyl hippuric acid,

Michaelis-Menten type metabolism, Animal scale-up

INTRODUCTION

Xylene is a clear, colorless, aromatic liquid.

This chemical is widely used as a solvent for paints, glues, printing inks, pesticides and adhesives, and as a componeRt of industrial and household productsi). The technical grade

of mixed xylenes is a mixture of all three

xylene isomers (o-, m-, p-) and varying

amounts ofethylbenzene, in which m-xylene is

the major component2).

Recently, biological monitoring

(biomonitor-ing) has beeR iRtroduced in the field of

industrial hygiene. Biological moni£oring ef

the work eRvironment is based on two con-cepts, biological exposure monitoring and

biological effect monitering3). Biological

expo-Received April17,1991

Accepted Mayl,l991

sure monitoriRg is designed to estimate the magnitude of exposure to chemicals or their

metabolites by means of their assay iR biologic-al samples, blood, urine, or expired air. In this

sense, biological monitoring complemen£s en-vironmental monitoring, i.e., measuring the concentrations of chemicals in the work en-vlrokment.

Biological effect monitoring is designed to predict the early health effects ef chemical exposure throiigh ana}ysis of biological sam-ples. Measurement of 6-aminolevulinic acid in

urine or 6-aminolevulinic dehydratase in

erythrocytes after exposure to lead, and

measurement of 62-microglebulin iB urine

after exposure to cadmium are examples of

biological effect monitoring.

However, biological monitoring of organic solvents means only biological exposure

(2)

128 T, Kaneko, K. Endeh, and A. Sato

since no appropriate markers are available for

eai"ly assessment of their health effects.

Basic knowledge about absorptioR, distribu-tion, metabolism, and excretion of the

chemic-al is essentichemic-al for interpretation of the vchemic-alues

obtained by biological exposure monitoring.

However, to date there have been only a

limited number ef reports4rmiO) concerning the

pharmaeokinetics of xylene in humans. Understanding of the pharmacokinetics of

organic solvents is facilitated by the use of physiological modelsii"i4). This method eB-ables us to analyze the pharmacokinetic pro-cesses of solvents iR humans by incorporatiRg both human physiological parameters (alveolar

ventilation, cardiac output, tissue volume,

tis-sue blood flow, etc.) aRd physicochemical o}-biochemical properties of the chemical (bloodl

air partition coefficient, tissuelblood partition

coefficients, metabo}ic constants, etc.). The

present study was intended to develop a

physiological simulation model of m-xylene pharmacokinetics in humans.

MEmoDs

1. Pdysiological Pharmacokinetic model for m-xylene

Our model is based oR the geReral

assump-tion that the body is composed ofseveral tissue groups connected to each other via the

circula-tion. The tissue volume aRd the blood fiow are equivalent to those in the living body, heRce the model is called "physiological".

Figure I shows a physiological

pharmaco-'i inetic model for m-xy!eRe. With appropriate

modifications, it can be applied to other

orga-nic solvents. The model consists of 7

compart-mentsi5): the lung compartmeRt (LC)

com-posed of the Iung tissue, arterial blood, and

one-third of the tidal volumei6), the vessel-rich

compartmeRt (VRC) cemposed of the brain,

heart, kidneys and glandular tissues, the

ves-sel-poor compartment (VPC) composed of

tissues includiRg the red bone marrew, the

muscle compartment (MC) composed of

mus-VLCL

QcCLX

LC

VRCR

QRCR/LR

QRCL?v

VRC

vpcp

QpCp/Lp

QpCLX

vpc

VMCM

QMCM/LM

QMCLX

MC

VFCF

QFCF/LF

QFCL)k,

FC

ShuntQsCLX

VGCG

QGCL7v

GC

VHCHQGCGILG

QHCL)v

HC

(QH+QG)CH

LH-"---]i・:Kmi+CH

lww""riFi-T'A"""'1

Vmaxi-CH

--A - d-- -m -

--m-M HA

Kex

Fig. I.

m・-MHA in urine

A physiological pharmacokinetic model

for the transfer of m-xylene. LC, lung compartment; VRC, vessel-rich tissue com-partment; VPC, vessel-poor tissue

com--partment; MC, muscle comcom--partment; FC, fat compartment; GC, gastrointestinal

compartment; HC, liver compartment. C,

concentration in mmol/l; V, volu}ne of

compartment in l; Q, fiow in llmin; L,

tissuelblood partition coefficient; A, bloodl air partition coefficient. Subscript O stands for inhaled air; C for cardiac output; L for LC; R for VRC; P for VPC; M for MC; F

fbr FC; G for GC; H for HC. rn-TA,

m-toluic acid; m-MHA, m-methyl hippuric acid; Kex, excretion rate constant of m-MHA in rriinwwi.

(3)

Physiological Pharmacokinetic IVIodel for m-Xylene 129

cles and skin, the fat compartment (FC)

com-posed of adipose tissues and yellow boRe

mayrow, the gastrointestinal compartment

(GC) composed ofthe portal system excluding the liver, and the hepatic compartment (HC).

The muscles and skin are regarded as an

iRdividual compartmeRt because the blood

flow in these tissues changes with body

move-ments. "Shunt" means arterioveRous shunt. These 7 compartments are coRnec£ed by the

blood fiow system.

Several assump£ions were needed to

simu-late the pharmacokinetics of m-xylene. First,

}'espiration was regarded as a contiRuous rather than a periodic process. Next, the

solveRt concentration iR the blood flowing out

of a given compartmeRt (veRous blood) was

regarded as equilibrated with the conceRtra-tion in that compartmei3t. For example, wher} the solvent concentratioR iB a compartment (i)

is defined as Ci, the solvent concexxtratioB in

the venous blood is assumed to be Ci/Li where

,

Li is the tissue/blood partitioR coefficient for

that compartment. Also, al} processes other than metabolism in the liver were represented

by linear expressions. No metabolism was

assumed to take place except in the liver, and eliminatioR of unchaRged selvent was assumed to occur only via expired air.

The metabo}ism of m-xylene in the liver was

expressed as a Michaelis-Menten process, i.e., v

= Vrnax・CHI(Km+CH), whei-e v is the }'ate of

metabolism aBd CK the intrahepatic

concen-tration of m-xylene.

Based on these asstimptions, the following differential equations were obtained by

ap-plying the law of mass actioB to the balaRce of

the compound in each compartmer}t. In the

luRg compartment,

dCL

V£ dt =QLCo+QRCRILR+QpCp/Lp

-l-<2bMCM/LM+<2!FCFILF

+(QG+QH)CH!LH

-(Qc-Qs)ACL-QLCL, (l)

in the hepatic compartment,

dCN

== QH A CL+<ll)GCGILG

VH

dt

-(QG+QK)CHILH

-Vmax・CHI(Km+CH), (2)

in the other compartments,

dCi .

Vi dt == QiACL-QiCilLi, (s)

where i : R, P, M, F, G (For symbols, see the

legend foi' Fig. I).

An outliRe of the metabolic pathway of

m-xylenei7) is shown at the bot£om of' Fig. 1.

m-Xylene is metabolized primarily to m-tolt}ic

acid (m-TA), which is then coajugated with glycine and excreted as m-methyl hippuric

acid (m-M HA) in the urine. The pathway frona

m-xylene to 2,4-xyJenol accounts for on}y

1-2% of the total amouRt metabolized7), aixl

this pathway was ignored to simplify the

model. Also, as mentioned later, conversion of

rn-TA to m-MHA was considered not to

regulate the metabolic p}-ocesses. In addition,

transport of the metaboiites was assumed to

occur within a singie compartment.

WheR the amount of m-MHA present iR the body t min after the beginning of m-xyleRe

inhalation is expressed as XMHA, the following equatlon can be derived.

dXMHA

ww-

dt :Vmax・CHI(Km+cH)

-KexXMHA. (4)

Let' the amount of m-M HA exc}"eted in uriRe by t min after the beginning of inhalation be

UMKA, then

dUMHA

ww-

dt :KexXMHA. (s)

Although the differential equatioRs (1)-(5)

cannot be solved analytically,

computer-assisted numerical analysis is possible. We

solved these equations by Euler's methocl using

a spreadsheet programi5). Parameters used in

the model (blood flow, tissae volume, partition coefficients, metabolic constant, initial coRcen-tration) are given in the fo}-m ofa tab}e (Model

description) and shoxKJn iR Fig. 2. The blood flow at rest or during exercise can be entered

(4)

l30 T. Kaneko, K. Endoh, and A. Sato

MOOELDESCRtPTION

Volume Lambda Bloodtiowelo Qc lnit Compartment

eleBW tissuelblood rest liht

2 " 1oe 204.807692 o tung 3 4.42 37.9 27.1 o richty 8.5 2.01 6.3 3.6 o poorly 41.5 3.01 11.4 31.8 o muscle 21.1 77.84 5.3 7.7 o tat - - 15.1 16.4 o shunt 1.9 4.67 17.1 9.5 o .gi 2.3 3.02 6.9 3.8 o liver BW(kg) (bloodlair) Qc(t) Qc(l) 70 26.4 5.79242393 10.4

Km(mmoVl)

Kex(minA-1) Km(mfnoUl>

O.33 O.O12 O.033

Vmax{mmol/min) Vmax(mmolimin)

e.21818505 O.02727313

CONTROL PANEL

start mindt .Incr intervat

o o.Ol 1.02 3 o

SCHEDULE

sto conc maxdt activit

30 O.O020486 O.5 rest

60 o O.5 rest

24e O.O040972 O.5 rest

300 o O.5 light

420 e.oo3e72g e.s light

480 o.eoo4og72 e.s light

1440 o O.5rest

REsuL`rs

time co Cl Cr c Cm ct c Ch

MHA

o o.ee2 o o o o e o e o

O.42 O.O02 4E-05 O.OO02 1E-05 6E-06 5E-06 O.OO02 5E--O5 1E-08 1.18 O.O02 8E-05 O.OO14 9E-05 3E-05 3E-05 O.OOI O.OO03 7E-07

.

2.6 O.O02 1E-04 O.O04 o.eoo3 O.OOOI 1E-04 O.O031 O,OO07 1E-e5 5.22 O.O02 O.OOOI o.eesl o.oeo7 o.oeo3 o.eoo3 O.O066 O.OO12 1E-04 10.1 o.eo2 O.OOOI O.O133 o.oe16 O.OO06 O.OO06 O.Ol19 e.oo2 o.eoo7 19 O.O02 O.OO02 e.O183 O.O032 O.OO14 e.oo14 O.O18 O.O029 O.O037 30.2 O.O02 o.eoo2 e.0211 o.oes O.O025 e.oo2s O.0216 O.O035 O.O124 30.3 o o.oee2 O.0211 o.oesl o.oe2s O.O025 O.e217 O.O035 O.O125

30.8 o O.OOOI O.0207 O.O051 e.oo2s O.O025 O.e215 O.O034 O.Ol3

31.7 o O.OOOI e.O194 O.O051 O.O026 O.O026 O.0205 O.O032 O.O14 33.4 o 9E-05 O.O167 o.eosl o.oe26 e.oo27 O.O185 O.O028 O.O159

36.4 o 7E-05 O.Ol26 O.O05 O.O027 O.O028 O.el49 O.O022 O.O196

42.1 o 5E-05 O.O079 O.O047 e.oo2s O.O03 O.Ol O.OO15 O.027

52.6 o 3E-05 O.O041 O.O039 o.oe2s e.oo32 O.O052 o.ooes' O.0413

60.5 o 2E-05 O.O03 o.eo34 O.O027 e.oo33 O.O036 o.eoos e.0519

60.6 O.O041 6E-e5 O.O031 e.oo34 O.O027 O.O033 O.O037 O.OO06 O.0521 61.2 o.oe41 O.OOOI O.O043 O.O034 O.O028 O.O033 O.O045 O.OO08 O.e529 62.3 O.O041 O.OO02 e.eo7g O.O036 O.O028 O.O034 O.O072 O.OO14 O.0543

Fig.2. Spreadsheet:"Modeldescription," "Control panel," "Schedule," and "Results".

into this spreadsheet. These values are re-gardecl as defaults Lmtil new values are

en-tered. The spreadsheet iRcludes 3 "Control

panel" and a "Schedule" for setting values such as exposure concentration, exposure tirr}e, and

differential interval (dt), which coRtrol the

calculations. The results are provided as a table in "Results" (Fig. 2). The differential eqtiations

were solved wi£h gradual incyeases in the

differential interval (dt) to save time. In

geRer-al, chaRges iR the concentration in each

com-partment are large at the beginRing of the

sirxiulatioR, requiring a small dt. However, as

the simulatiolt progresses, the changes iR the concentration decrease to nearly zero (steady

(5)

Physiologica

2. Simttlation Paranzeters

Parameters including the tissue volumes,

blood fiows, partition coefficients, metabolic

coRstants (Vmax and Km) and excretioR rate

constant are Beeded to rLm this inodel. The volume and the blood flow were calculated for

each compartment from the values of Davis

aRd Maplesoni8). The partition coefficients of in-xylene, Vmax and Km of rr}-xyleRe metabol-ism, aBd the rate constant of uriRary m-MHA

excretion were determiRed by the followiRg

experiments. The animal experiments were

performed in accordaRce with Guidelines for

Animal Experiments, Yamanashi Medical

Col-lege.

I) Partition coefficients of m-xylene

[I"he tissuelair partition coefficients were

determined using tissues from adult male

Wistar rats according to the method of Sato and Nakajinr}ai9). Tissue specimens were pre-pared according to Sato et al.ii).

2) Vmax and Km

The metabolic constant of m-xylene was

determined using hepatic microsomes of adult

male Wistar yats by measuring the rate of 3-methyl benzyl a}cohol (IV{BA) formation. The microsomes were prepared accordiRg to

Sato and Nakajima20).

The reaction mixture (O.5 ml) contained O.75 mg microsomal protein, l inM NADP, 20

mM glucose-6-phosphate (P), 2 tmits

G-6-P dehydrogenase, aRd 50 mM KIK-phosphate

buffer. The reaction was iRitiated by addiAg

m-xylene and was stopped after 10 min by

adding e.l ml each of 15% ZnS04 and

satu-rated Ba(OH)2. The mixture was then

ceRtri-fuged at 3,eeO rpm for 15 miR. The

super-gatant (20 pal) was anaiyzed for MBA by

high-performance liquid chromatography

(I-IPLC). The HPLC operating condi£ions

were: Column, Hitachi ODS, 4.6 mm O × 150

mm; mobile phase, 30% acetonitrile; flow rate,

1 mllmin; detection wavelength, 220 nm.

Under these conditions, the production of MBA liBearly increased with the microsomal

protein level up to }.O mg and with the

} Pharmacokinetic Model for m-Xylene 131

iRcubation time up to IO min.

3) Rate constant of m-MHA excretion (Kex)

m-TA aRd m-MHA were administered at

e.04 mmollrat via the tail vein to adult male Wistar rats. Urine samples were collected at predetermiRed intervals afte}' administration,

and the urinary m-MHA concentration was

measured according to the method of

Takeuchi et al.L'i). The urine was diluted with distilled watey to 100 ml, and was centrifugecl

at 3,Oee rpm for 5 min. The supernatant (20

pal) was analyzed for m-MHA by HPLC. The

HPLC operating conditions were: Column,

Hitachi ODS, 4.6 mm ep × 150 mm; mobile

phase, acetonitrile: distilled water: acetic acid: rs--cycloclext}'ine : 1OO: 900: 15: l5; flow rate, 1 ml!i'r}ifl; detectioA waveiength, 228 nm.

REsa"irs

1. Partition coe7[7icients of m-pc))lene

The {issuelair partitioB coefficieflts of rats

obtained from this experiment are shown in

Table 1.

The tissue/blood parti£ion coefficients for humai}s were calcLilated as the rat tissuelair partition coefficients divided by the human bloodlair partition coefficieRt (Table 2). The

value reported by Sato aRd Nakajimai9) was

used as the human blood!air pa}"tition

Table1. perimental results determiRed using

rats. Tissue Tissue/air (Mean±SD) Tissue/bloo(l Lung Brain Heart Kiclney Testis Muscle Fat Intestine Spleen Liver Blood 108 ± 24.1 107 ± 12.6 76.5± 21.0 151 ± 5.61 53.2± 16.9 79.7± 20.2 2050 ±459 129 ± 2.72 58.3± 17.0 79.9± 9.42 39.9± 7.18 2.70 2.68 192 3.78 1.33 1.99 51.5 3.23 1.46 2.00

(6)

l32 "lr. Kaneko, K. Endoh, altd A. Sato

ficient.

2. Ymanc and Km

This experiment indicated the presence of

two different pairs of Vmax and Km

(Vmax} = O.6×IOmu3 mmollliverlmiR, Kmi :

O.038 mmolll; Vmax2 == 4.8×IOrm3 mmollliverl

min, Km2 :O.380 mmolll) at high and low

substrate coRceRtrations, respectively (Fig. 3).

These two pairs of Vmax and Km values were

used in our simulation study. Ilrhe Vmax

derived frorn }'ats was corrected for body

surface area, (body weight)O'7, while the Km was used directly.

3. Rate constant of m-MHA esccretion (Kex) The excretion rate constant was determined

from the slope of the cumulative excretion

curve (Fig. 4). There was no sigRificakt

differ-ence betweelt the m-MHA excretion rates

determined after administration of m-MHA

and m-TA, a finding which suggests that

conversion of m-TA to m-MHA does Rot

regi-}late the rate of m-MHA excre£ion. On the basis of this experiment, the uriRary excre£ion

rate cons£an£ (Kex) of m-MHA was

deter-mined te be O.O12 min"i. This value was used

in the simulation study as the value for

humans.

4. AgTeenzent betzueen the simulated and human ep<4)erimental data

Table 2 summarizes the basic parameters

used in the simulation. Simulations were per-formed for a man weighing 70 kg who inhaled

Table 2. Simulation parameters for m-xylene pharmacokinetics in man.

Compartment Volttme"), l Bleed fiOwll), llmin Partmon coefficienti') (tissuelblood) Lung (LC) Vessel-rich (VRC) Vessel-poor (VPC) Muscle (MC) Fat (FC) Gastrointestinal (GC) Hepatic (HC) Shunt V L`) O.030Bwd)

O.085BW

e.415BW

O.211BW

O.O19BW

O.023BW

Qc

O.379Qc O.063Qc O.114Qc O.053Qc O.171Qc O.069Qc e.151Qc 4.e9 4A2 2Dl 3.01 77.8 4.67 8.02

Bloodlair partition coefficient (A)e) Cardiac output (Qc)ii), l/niin

Vmaxb)f),mrr}ollmin Vmaxi

Kmb), mmolll KMi

O.033

Kexb), min-i

Q.

26.4 O.296 I.394×lO-3(Bw)(}・7 O.O12

Qc

(Bw)O,7

Vmax"

1.1l5×10-L)(Bw)O・7 I<mL, e.3se a) b) c) d) e) b Reference 18. Experimentally determinecl.

Vr. = Functional residual capacity + l13 of tidal volume -i- volume of arterial bloocl × A + volunae of lung tissue × lunglair partition coefficient (Reference

l6).

Body weight iR kg. Reference I9.

Extrapolated froi/rt yat data as follows: (Viir}ax of rats) × (BW of humanslBW of

(7)

Physiological Pharmacok}netic Model for m-Xylene 133

A

x・ .s E "x o E E

Y

b

'6 -o ot

>x

'

sooe

6ooe

4ooe

2000

o

m

o Ml a -40 m ur

Vniax x e.6 x 10-3 mmo{/min

Km =O.033 mmolll

-2G

m

B

o 2o 4e 6o

1/Substrate concentration, (mmolll>'i

=・ .E E

>

o E E

v

s

・.-" e o -di

>

)

12oe

Vmax = 4.8 x 1O-3 mmollmin

Km .-.. O.330 mrrIolfl

900

600

3oe

-5 .

Fig. 3. o di-,a,m,-Fl-D -o E

40

E O-.Ets .g 3o

<

i

s

6 20

= .9ms ts

X 10

.sg・

go

o

X 10-3

80

m

1OO

e -o /j"

T

4-3 -2 -t O12345

1/Substrateconcentration,(mmolll)-i

Double reciprocal plots of metabolic velocity against subs-trate concentration. A, Vmax and Km at low subssubs-trate con-centrations. B, Vmax and Km at high substrate

concentra-tions. O.0329 x O - e・o.ot2 t> c#tpax.tT.nd'-IL'eeek'"'-,'ssY

x

""'pt 'i'・' L g"-・'・-・'・"1}・・・t.・}mx---i

i-i-7

K

O.0307 x (1 - e-o.oi2 t) - Catculated <m-TA> ::::ssthk:: Catculated (m-MHA) M Observed (m-TA} o Observed (m-MHA) Fig. ・---

Tjme after injection, h

4. m-MHA excretion after i.v.

m-TA and m-MHA.

8 tO

iojection of

100 ppm m-xylene for 6 hours (9:OO-12:OO

and l3:OO-l6:OO) in accordance with the

re-port of Riihimaki et al.7). The blood

coRcentra-tion was expressed as the concentracoRcentra-tion in the

blood flowing out of VRC.

The values resulting frorn this simulation

were iR geReral agreement with the hurnaA

experimental data reported by Riihimaki et al. (Fig. 5).

DIscussloN

The greatest advaRtage of a physiological

model is that experimental data obtained from animals can be extrapolated to hurnans}4). The volume of each tissue is convertible between

(8)

134 T. Kaneko, K. Endoh, and A. Sato =t--oE E v" o

9

n

・=--=

9

rs t: =o o = o o e =

9

ptts ff x IO-3 20 le o m o "

A

- Simulated a Observed -o

E8

E o" -"ts .g 6

E

¥

Eo 4 ・9e tO. 2 .it N -= E

8

OioQ ,v o

48

Time after the start of exposure, h

ca 12

B

n - Simulated a Observed Fig. 5.

8 16 24

Time after the start ef exposure, h

Comparison between experimentally

observed and simulated m-xylene

phar-macokinetics in humans. The

ex-perimental data were adapted from

Re-ference 7. A, m-xylene concentration in blood. B, m-MHA excretion in urine.

weight ratio and the blood flow from the body surface area. The metabolic coRstant in hu-mans can also be estimated from the values iR small animals, because the Michaelis constant

(Km) is considered to be the same iR beth small

aRimals and humans, and the maximum

veloc-i£y (Vmax) is assumed to be proportional to the

body surface area. However, since there is no appropriate method to extrapolate the urinary

excretion rate constant, it is assumed that the

rate constant is the'same in humans and

animals.

In our present model, the voltune aBd the

blood fiow were calculated for each compart-ment frem the values in the literaturei8). The

partition coefficieltts, metabolic constants, and

the rate constant of urinary m-MHA excretion

were de£ermined from aBimal experimeRts. The results of the simulation using these parameters were in general agreen}ent with

human experimental data (Fig. 5). Therefore, this model is appropriate for predicting the pharmacokinetic behavior of m-xylene in

hu-maRs.

Knowledge of toxicokiRetics of chemicals is the basic requiremeRt for uBderstandiRg the

relationship between exterRal and internal doses. The physiologically based

pharmaco-kinetic model preseRted here can be used to

gain insight into the kinetic behavior of

orga-Ric solven£s in humaRs.

Factors such as body build, physical exe}℃ise,

etc. can alter the toxicokinetic profiles, and

thus the relationship between extemal and

inteynal doses. Physiologically based pharma-cokinetic models pyovide us with particularly useful information in this regard. Application of our model to elucidate some kinetic aspects of human exposure to organic solvent vapors

will be discussed iR detail in the accompanyiRg paper22>.

REFERENCES

1) Coildie LW, HillJR, BorzellecaJF. Oral icology studies with xylene isomers and mixed

xylenes. Drug Chem Toxicol 1988; ll:

329-354.

2) NationalInstituteforOccupationalSafetyand

Health, Criteria for a recommended standard.

Occupational exposure to xylene. HEW

lication No. 75-168, Washington, D.C., U.S.,

1975.

3) BernardA,LauwerysR.Generalprinciplesfor biological monitoring ofexposure to c}aemicals. In: Mat HH, Dillon HK, eds. Biological

toring of Exposure te Chemicals. New York, Chichester, Brisbane, Toronto, Singapore: John Wiley & Sons, 1987: I-l6.

4) Ogata M, Takatsuka Y, Tomokuni K.

tion of hippuric acid and m- or

methylhippuric acicl in the urine of persons

(9)

Physiolegical Pharmacokinetic Model for m-Xylene 135

exposed to vapours of toluene and m- or

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,

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'

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lncl Health 1989; 31: 335-341.

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lic chemicals. Drug Metabol Rev 1984; l5: 1033-I070.

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18)

tification of a physiological model of the tribution of iojected agents and inhaled thetics. Br J Anaesth 1981; 53: 399-405.

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Improved high performance liquid

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Table 2. Simulation parameters for m‑xylene pharmacokinetics in man.

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