Document 4aj11nVb833NwKJQKMyDDNzRQ
Vol. 23, N . 41980
It'f
// A-r h7
c
Tbe Title Sectioo/Volume Contents and Subject/Author Index for^UQ
are Inserted loose in this issue.
u
AN INTERNATIONAL JOURNAL PUBLISHED FOR THE BRITISH OCCUPATIONAL HYGIENE SOCIETY
Contents
S. J. Silk : President: The British Occupational Hygiene Society, 1980-1981 326
E. Bye, G. Edholm, B. Gylseth and D. G. Nicholson : On the determina
tion of crystalline silica in the presence of amorphous silica
. 329
M. A. Pinches and R. F. Walker: Determination of atmospheric con* taminants using a continuous paper-tape personal monitor--I. Analysis of aromatic amines............................................................................335
A. Morgan, A. Black, N. Evans, A. Holmes and J. N. Pritchard:
Deposition of sized glass fibres in the respiratory tract of the rat
353
R. C. Brown: The behaviour of fibrous filter media in dust respirators, 367
J. R. Hoyes and R, Clayton : A routine for the control of the performance
of microscopists evaluating airborne asbestos fibre samples on
membrane filters by phase contrast microscopy
.381
BOHS Annual Conference 1980, held in Newcastle upon Tyne, 15-18 April 1980. Some papers presented............................................... 403
D. Gompertz: Solvents--the relationship between biological monitoring strategies and metabolic handling. A review...................................... 405
Y
i
'*.v
I nlQ M1
c COD^V-
t&on outsider bbaa<ck cover)
ISSN 0003-4878 AOHYAS 23(4) 325-442 (1980)
PERGAMON PRESS
Oxford ' New York * Paris * Frankfurt
SL 026769
Am. oecup. Hyp. Vol. 23. p. 405-410. Perjamon Prtu Ltd. 1980. Printed in Greet Briuin
0003-4878/80/1201-0405/502.00/0
SOLVENTS--THE RELATIONSHIP BETWEEN BIOLOGICAL MONITORING STRATEGIES AND METABOLIC HANDLING
A REVIEW
D. Gompertz
Occupational Medicine & Hygiene Laboratory, Health & Safety Executive, 403 Edgware Road, London NW2 6LN
Abstract--The risk to an individual worker from exposure to an organic solvent is more directly related to the uptake of the solvent than its level in the atmosphere. Uptake varies from worker to worker, depending on exercise, respiratory fitness and the amount of stored adipose tissue. Clearance and metabolism of a solvent also vary between individuals, being afTected by genetic and environmental factors. Uptake may be estimated by measuring the solvent or its metabo lites in breath, blood or urine, but any sampling strategy must be designed to exclude unnecess ary variation introduced by different metabolic handling rates occurring in individual workers.
The biological effects of organic solvents relate more directly to the amount absorbed than to the concentration in the working atmosphere and, as there are large inter individual variations in solvent uptake under any specific exposure conditions, it follows that a better estimate of individual risk can be obtained by measuring uptake rather than exposure. Although uptake, excretion, metabolism and clinical effects of organic solvents have been investigated extensively (see reviews by Astrand, 1975; Piotrowski, 1977; Savolainen, 1977), it is not easy to find a sensible and coherent strategy for monitoring either the uptake or the effects of organic solvents in an industrial setting. The studies described in the literature vary from elegant experimental exposures to industrial surveys designed to correlate personal monitoring data with biological measurements. There are also several theoretical studies using modelling systems to describe the pharmacokinetics of solvent elimination from the body (Fernandez et al., 1977; Sato et a/., 1977). In this paper it will be argued that the metabolism of the solvent and the effects of external factors modifying its metabolism must be taken into account when establishing a monitoring strategy. The term metabolism is used here in its widest sense to include uptake, distribution, biotransformation and ex cretion.
There are many reports in the literature presenting the results of surveys in which personal exposure data are correlated with measurements of the solvent or its meta bolites in breath or biological fluids. Typical of such investigations are those reported by: Norseth (1974), styrene exposure in the glass-reinforced plastic boat industry; EngstrOm et al. (1978), xylene exposure in painters; Brugnone et al. (1976) and Veulemans et al. (1979), toluene in rotogravure workers; and Perbellini et al. (1977), dichloromethane in the shoe industry. The results of these studies show that there is
Crown Copyright 1980.
405
SL 026770
406 D. Gompertz
a wide spread in the distribution of the biological data at any individual exposure level. The degree of spread reflects the problems of defining a sampling strategy to allow for inter-individual differences in metabolism and elimination of the solvent concerned. The major factors affecting solvent uptake and metabolism are listed below:
(i) Partition between air/blood and blood/fat (ii) Pulmonary ventilation--respiratory rate
--fitness --exercise (iii) Fatness or thinness of the individual (iv) Work-practices (route of exposure) (v) Drugs and alcohol (vi) Addiction/aversion to the solvent (vii) Inter-individual variation in metabolic clearance rates (genetic variability)
Although the partition coefficient for solvents between air and simple aqueous systems is characteristic of that solvent, Perbellini and his colleagues (1977) showed that the partition coefficient of dichloromethane between blood and air depends on the circu lating triglyceride concentration in the blood, introducing a further variable into pharmacokinetic studies. It is important to establish the underlying biochemical vari ability in solvent metabolism once differences in respiratory function, work practices, personal habits and obesity have been excluded. Evidence of the extent of this residual variability is available from pharmacokinetic studies of drug metabolism. In such studies detailed and accurate information about exposure (dosage) is readily available; the investigators can monitor the patients taking the tablets (see for example Walle et al., 1978). Exposure is continuous, 7 days a week; measurements can be made when the subject is under steady-state conditions, and a precise sampling strategy can be devised. Even under these tightly controlled conditions of exposure and sampling there is considerable residual variation. Much of this is undoubtedly due to genetic dif ferences in drug metabolism, as had been shown from identical twin studies. (Vessell, 1977). This residual variability is such that it is impossible to estimate dose (exposure) accurately from the concentration of the drug in the plasma or other body fluids.
It is accepted in pharmacology that the concentration of a drug in the plasma is related to uptake (absorption) and correlates with biological effect better than other measurements (Turner, 1978) and this extends both to therapeutic and to toxic effects. It may be suggested that, although biological monitoring measurements do not cor relate accurately with exposure, they do relate to uptake and toxic effect in the exposed person.
While examples from clinical pharmacology show the minimum degree of biological variation to be expected under tightly controlled clinical conditions, experimental studies of solvent exposure provide evidence of the minimal variability that can be expected under industrial conditions. Investigations of methylene chloride excretion in breath and carboxyhaemoglobin production following experimental exposure (Stewart et al,, 1976; Peterson, 1978) show the degree of variation in biological measurements to be expected under controlled environmental exposures. These studies involved exposure of a sedentary group of normal volunteers, but in a series of elegant studies Astrand and her colleagues (1975) have documented the effects of exercise on solvent uptake. For some solvents there is a consistent and considerable increase
in uptake is a mini
A pn different investiga selected was a di pose tiss biologic: obese su depends blood ar
Any individu; ables du designin or a met blood, u are inter The cho trichlorc product: metabol and blo< compart monitor should r et al. (I1 post-exp breath c shift. Sa uptake : suggeste
xposure level. .>y to allow for nt concerned, elow:
: variability)
jueous systems lowed that the s on the circu variable into ichemical varivork practices, of this residual oli^kn such idil^Kailable; xample Walle be made when strategy can be sampling there to genetic difidies. (Vessell, Jose (exposure) body fluids, i the plasma is tter than other to toxic effects, nts do not cort in the exposed
ee of biological i, experimental ity that can be .oride excretion ental exposure >n in biological is. These studies series of elegant ects of exercise Jerra^Uj^^iintcrease
Biological monitoring for solvent exposure
407
in uptake with increasing exercise (up to a 5*fold increase), whereas with others there
is a minimal effect. A proportion of the variability in the uptake of a solvent is due to the effect of
different amounts of adipose tissue between subjects. Carlsson and Lindqvist (1977) investigated toluene uptake during varying degrees of exercise in seven male subjects selected to cover the thin and excessively overweight ends of the population. There was a direct correlation between toluene uptake and estimates of the amount of adi pose tissue for each subject. EngstrOm and her colleagues (1978) have shown longer biological half-lives for methyl hippuric acid excretion following xylene exposure in obese subjects. Thus experimental studies have shown that uptake of any solvent depends on pulmonary ventilation (affected by exercise and fitness), its solubility in blood and tissues and the relative size of adipose tissue depots.
Any biological monitoring programme should be able to indicate differences in individual uptake rather than exposure, but should not be affected by random vari ables due to poorly designed sampling strategies. The questions to be answered in designing a biological monitoring programme include: should one measure the solvent or a metabolite of the solvent; which medium should one use for analysis (breath, blood, urine) and when should the samples be taken? The answers to these questions are inter-related and depend on the metabolic fate of the solvent under consideration. The choice of the solvent or a metabolite may be limited, as in the case of 1,1,1, trichloroethane where there is only a small percentage of conversions to metabolic products, or there may be an embarrassment of choices (Table 1), due to extensive metabolic transformation. Although the clearances of trichloroethylene from breath and blood are similar, the elimination of solvent and metabolites from each tissue compartment follows a different time course (Fig. 1). It is important to choose a monitor of uptake that gives a reasonably damped measurement: the measurement should not just reflect exposure during the few minutes prior to sampling. Stewart et al. (1974) have shown that solvent concentrations in breath in the first few hours post-exposure reflect end-of-shift exposure levels and only after 12 h post exposure do breath concentrations relate to the time-weighted average exposure for the complete shift. Sampling should be designed when possible to give a longer-term measure of uptake and thus, perhaps, risk. In the case of trichloroethylene exposure, it could be suggested that measurement of trichloroacetic acid excretion on the 4th or 5th day of
Table 1. Trichloroethylene exposure--biological
monitoring
Analyte
Medium Time of sampling
Trichloroethylene
Breath
Blood
Trichloroethanol Trichloroacetic acid
Blood Urine Urine
End-of-shift and/or next day
End-of-shift and/or next day
End-of-shift
End-of-shift (4th or 5th day)
SL 026772
408 D. Gompertz TRICHLOROETHYLENE--DISTRIBUTION AND METABOLISM
Fig. 1. The time course of the elimination of trichloroethylene and its metabolites from various body compartments. The concentrations are in arbitrary units and are not related to the amount of trichloro ethylene or its metabolites in individual compartments. This model is drawn from the work of
Fernandez et at. (1977).
the working week would give the best integrated measure of uptake; the `day-of-theweek' effect being used intentionally to give a measure of biological effect over a longer period.
Although measurement of concentration of-solvent in expired air is seriously affected by short-term changes in exposure and exercise prior to sampling, breath analysis still has an attraction. This technique is non-invasive, acceptable to the work force and the samples can perhaps be analysed in the same way as atmospheric airsamples. The problem of sampling-time still has to be solved. Measurement of expired air concentrations 12-16 h after the end of exposure, that is at the beginning of t le next shift, would appear to give the best indicator of uptake during the previous shift. However, with maximum exposures in the 100 ppm range, the concentration of solvent in breath 12 h after exposure is frequently less than I ppm. Although there is little information in the literature describing the performance of breath sampling devices at these low concentrations, Pasquini (1978) has documented considerable losses of trichloroethylene and perchloroethylene from breath samples by absorption on to the glass walls of breath collection tubes. It appears there is some urgency to establish robust methods for both collection of alveolar-air samples under industrial conditions and also their analysis at these sub-part-per-million concentrations. Once satisfactory sampling and analytical methods have been developed, it will be possible to set up epidemiological surveys to correlate this data with clinical changes especially from the point of view of central nervous function.
Until satisfactory breath analysis methods are available, we will have to rely on other biochemical makers, for example urinary trichloroacetic acid or trichloroethanol for trichloroethylene exposure, carboxyhaemoglobin for methylene chloride
exposure,
be aware interpreta
(1976) shi acid exert after exp> workers;
achieve a In sur
of exercb mentally bolism of strategies cretion. 1 unreprest
Astrand, 1 199.
Brugnoni and bit
Carlsson, Emirm
Engstrom concen Scand.
Engstrom to xylei
Fernandf Simula 34, 43.
NoRSF TH,
PaSOL'INI, //iff. A
PFRBFI-LIN
and bit Hhh 41
Pfitrson,
j Am. hi
j PlOTROWSl
Depart i Sato. A,, ; the cxc
Jj 34, 56. Savolainf ; toxic e
Stfwart. i ethyler
Stewart, ? expose
Turner, I cologit Shane
Vessel, E Theraf.
OLISM
"\TCE TRI/FAT
24 HOURS
rom various body lount of trichloro-om the work of
mc he *^^of-the;t over a longer
iir is seriously mpling, breath le to the workmospheric airnent of expired lingofne next previous shift, ition of solvent n there is little iling devices at rable losses of otion on to the cy to establish rial conditions ice satisfactory sible to set up dally from the
ave to rely on or trichloro-
tylene chloride
Biological monitoring for solvent exposure
409
exposure, and methyl hippuric acid excretion after xylene exposure. It is important to be aware of the way in which individual variability in metabolic clearance rate affects interpretation of data. Our data (Wilson et al,, 1979) and data from Engstrom et al. (1976) show the degree of inter-individual variability in the time-course of mandelic acid excretion after styrene exposure. It is not possible to select any one specific time after exposure that will give a urine sample that will reflect peak excretion in all workers; it is necessary to collect all urine passed over a period of several hours to achieve a representative sample.
In summary, the uptake of a solvent depends on respiratory function, the effects of exercise and the amount of stored adipose tissue, while genetically and environ mentally determined pharmacokinetic factors control the rates of clearance and meta bolism of the solvent. Measures of uptake are available for many solvents, but sampling strategies must take into account the time course of metabolite production and ex cretion. Disregard of the kinetics of solvent metabolism when sampling results in unrepresentative data that neither reflect exposure, uptake nor risk.
REFERENCES
Astrand, I. (1975) Uptake of solvents in the blood and tissues of man Scand.J. Work Environ. Hlrh 1, 199.
Brugnone, F,, Perbellini, L., Grigolini, L., Cazzadori, A. and Gaffuri, E. (1976) Alveolar air and blood toluene concentration in rotogravure workers. Ini. Arch, occup. Environ. Hlth 38, 45.
Carlsson, A. and Lindqvist, T. (1977) Exposure of animals and man to toluene. Scand. J. Work Environ. Hlth 3, 135.
Engstrom, K,, Harkonen, H., Kaluokoski, P. and Rantanen, J. (1976) Urinary mandelic acid concentration after occupational exposure to styrene and its use as a biological exposure test, Scand. J. Work Environ. Hlth 2, 21.
Engstrom, K... Husman, K., Pfaefli, P. and Riihimaki, V. (1978) Evaluation of occupational exposure to xylene by blood, exhaled air and urine analysis. Scand. J. Work Environ. Hlth 4,114.
Fernandez. J. G., Droz, P. O., Humbert, B. E. and Caperos. J. R. (1977)Trichloroethylene exposure. Simulation of uptake, excretion and metabolism using a mathematical model. Br. J. Ind. Med. 34,43.
Norseth, T. (1974) Styrene exposure during glass-reinforced plastic boat manufacture. Kjemi 34, 11, Pasquini, D. A. (1978) Evaluation of glass sampling tubes for industrial breath analysis. Amcr, Ind.
Hyg. Assn. J. 39, 55.
Perbellini, L., Brugnone, F,, Grigolini, L., Cunegatti, P. and Tacconi, a. (1977) Alveolar air and blood dichloromethane concentration in shoe sole factory workers. Int. Arch. Occup. Environ. Hlth 40,241.
Peterson, J. E. (1978) Modeling the uptake, metabolism and excretion of dichloromethane by man. Am. Ind, Hyg. Ass. J. 39, 41.
Piotrowski, J. K. (1977) Exposure tests for organic compounds in industrial toxicology. U.S. Department of Health, Education & Welfare Publication DHEW (NIOSH) No. 77-144.
Sato, A., Nakajima, T., Fujiwara, Y. and Murayama, N. (1977) A pharmacokinetic model to study the excretion of trichloroethylene and its metabolites after an inhalation exposure. Br. J. Ind. Med. 34, 56.
Savolainen, H. (1977) Some aspects of the mechanisms by which industrial solvents produce neurotoxic effects. Chem. Biol. Interactions 18, 1.
Stewart, R. D., Hake, C. L. and Peterson, J. E. (1974) Use of breath analysis to monitor trichloro ethylene exposure. Arch. Environ. Hlth 29, 6.
Stewart, R. D., Hake, C. L. and Wu, A. (1976) Use of breath analysis to monitor methylene chloride exposure. Scand. J. Work Environ. Hlth 2, 57.
Turner, P. (1978) Some aspects of the relationship between plasma drug levels and their pharma cological effects. In: Recent Advances in Clinical Pharmacology (Edited by P. Turner and D. G. Shand) Churchill-Livingstone, London.
Vessel, E. S. (1977) Genetic and environmental factors affecting drug disposition in man. Clin. Pharm. Therap. 22, 659.
SL 026774
410 D. Gompertz
Veulemans, H., Van Vlem, E., Janssens, H. and Masschelein. R. (1979) Exposure to toluene and urinary hippuric acid excretion in a group of rotogravure workers, Int. Arch, occup. Environ. Hlth 44, 99.
Walle, T., Conradi, E. C., Walle, U. K., Fagan, T. C. and Gaffney, T. E. (1978) Predictable rela tionship between plasma levels and dose during chronic propanolol therapy. Clin. Phorm. Therap. 24, 668.
Wilson, H. K,, Cocker, J., Purnell, C. J., Brown, R. H. and Gompertz. D. (1979) The time course of mandelic and phenylglyoxylic acid excretion in workers exposed to styrene under model condi tions. Br. J. Ind. Med. 36, 235.
DISCUSSION
Dr Henderson: You mentioned drugs and alcohol as factors. Would you comment on the effects of food intake patterns on biological measurements of exposure. There are wide variations in food intake that may affect metabolism and excretion of many materials involved in occupational exposures.
D. Gompertz: Several recent studies have shown the effect of diet on hepatic enzyme induction and the rate of metabolism of xenobiotics. One would therefore expect the rate of clearance of in dustrial chemicals to be affected to some extent by dietary variations.
D. Asker-Browne : In view of your comments on biological monitoring to determine the uptake of styrene, is a company achieving anything by doing a single urine test on each laminator every 6 months?
D. Gompertz: A single random urine measurement will give some indication of uptake, even if not at all precise. Those workers with excessive exposure and uptake will obviously excrete more mandelic acid than those with minimal exposure. I would suggest that there should definitely be some correction for urinary concentration (i.e. creatinine): an uncorrected random sample would give little information.
A. Berlin: This paper is a most valuable and timely contribution; however, the author should not be so pessimistic in his conclusions.
Biological monitoring should be viewed as a useful tool for both exposure assessment for epidemiological studies and for `control* purposes.
At the European Community level, there is considerable interest in this area. A series of mono graphs on biological monitoring is currently being published; an intercomparison programme is under way and an international seminar on ambient and biological monitoring is planned for December 1980.
D. Gompertz: I am not at all pessimistic about the value of biological monitoring. However, its importance will not be appreciated until it is realized that biological measurements reflect uptake and not exposure, and if poor and non-representative biological samples are taken because of a lack of awareness of pharmacokinetic principles. The comparisons between exposure data and biological measurements regularly found in the literature show that many authors are still unfortunately trying to use biological measurements to indicate the atmospheric levels of contaminants to which the individual worker has been exposed.
W. H. Walton: If the relation between airborne solvent concentration and uptake is poor, parti culates will be even worse.
D, Gompertz: I agree. M. F. Claydon: Could you please indicate the extent to which you foresee biological monitoring criteria being developed during the next few years. D. Gompertz: I see greater emphasis being placed on biological monitoring methods, allowing more detailed risk assessments to be made for individual workers. There are numerous instances in which significant uptake of toxic materials has occurred in spite of low air-levels of the contaminant in question. Biological monitoring will establish when workers have had significant exposure through the non-respiratory routes and when there has been intermittent failure in hygiene procedures. The difficulties in setting suitable levels will probably be eased by co-operation at the international level. This will allow enough statistical information to be collected rapidly and suitable biological control limits to be set.
Abstr physf of ren to mi blood effect^ their a flue cause Physi. showi minut brief t about tissue Const eiimir mode were > scriot
A MIXTi solvent xylene ; environ particul and per
Xyte ppm (C in the r; symptor the corn acute x; concent i nervous xylene-s workers disturba
SL 026775]
