Assessment of occupational health risk from multiple exposure: review of industrial solvent interaction and implication for biological monitoring of exposure.

37

ASSESSMENT OF OCCUPATIONAL HEALTH RISK FROM MULTIPLE EXPOSURE: REVIEW OF INDUSTRIAL SOLVENT INTERACTION AND IMPLICATION FOR BIOLOGICAL MONITORING OF EXPOSURE ROBERT TARDIF, RAJ GOYAL, AND JULES BRODEUR

Département Faculté de

de Médecine du Travail et d’Hygiène du milieu Médecine, Université de Montréal, Canada

This review is a critical survey and evaluation of recent literature on solvent interactions for the assessment of health risk. It addresses the implications of multiple solvent exposures 1) by examining the influence of solvent-solvent and ethanol-solvent interactions on the biological indices of chemical exposure, and 2) by indicating how the eventual modifying effects can be considered in the biological monitoring of mixed exposure. Reviewed studies reveal the effects of toxicokinetic interactions on the biological parameters, and the gaps in our knowledge. The measurement of potentially toxic molecular species is suggested for the biological monitoring of multiple chemical exposure. This approach appears to be important for drawing better quantitative conclusions on the internal exposure to biologically active chemical species. Finally, research needs arising from the critical analysis of the literature are briefly described. INTRODUCTION In the occupational environment, encounters with multiple solvents far outnumber encounters with single solvents. In the industrial sphere, several solvents commonly occur together, in various combinations, for example in paints, cleaning agents, plastics, perfumes, dry cleaning, printing and textiles. A study, pub1. Address all correspondence to: Jules Brodeur, Département de médecine du travail milieu, Faculté de médecine, Université de Montréal, Québec, Canada, H3C 3J7. 2. Key words: mixtures, interaction, biological monitoring, solvents, risk assessment.

Downloaded from tih.sagepub.com at UNIV NEBRASKA LIBRARIES on December 31, 2014

et

d’hygiène

du

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lishcd by the European Economic Community in 1980 (Thompson, 1982) shows that aliphatic and aromatic hydrocarbons constitute approximately 50% of all the solvents used in industry. Metal cleaning and dry cleaning activities mainly

halogenated hydrocarbons, e.g., trichlorocthylene, 1,1,1-trichloroethane, tetrachtoroethylenc. The paint industry is a very important user of solvents. Certain types of paints may contain different combinations of several of the following solvents: toluene, xylene, butanol, ethyl acetate, and ethylene glycol. Stoddard solvent, commonly known as mineral or white spirits, is a mixture of straight and branched chain paraffins, naphthenes, and alkyl aromatic hydrocarbons (Carpenter et al., 1975). Another type of solvent association common in the plastic industry is a mixture of acetone and styrene. The use of a combination of dichloromethane and methanol in the formulation of paint remover is quite recent (Gosselin et al., 1975). Sometimes, ethanol is also used as an industrial solvent, but exposure to ethanol generally occurs through ingestion during or after work hours. The widespread use of a mixture of solvents points towards the importance of studying ways to elucidate health risks due to multiple use

solvent exposure. It is now well documented that the biological activity of a given chemical can be considerably modified by prior or simultaneous exposure of a person to another compound (Hodgson, 1980; Murphy, 1980; Bingham and Morris, 1988). There is a considerable amount of literature on drug interactions; however’ the available information on industrial chemical interactions is rather scanty, and draws more attention towards the adverse health effects (Freundt, 1982; Ikeda,

1988). Mechanisms of interactions of chemicals in the body can be of toxicokinetic and/ or toxicodynamic type. Toxicodynamic interactions occur at the level of receptors or in the target organs at the molecular sites responsible for producing biological effects (Lu, 1985). Toxicokinetic interaction pertains to interference in absorption, distribution, biotransformation, and excretion of chemicals. Any stage of metabolism can be affected by another chemical or its metabolite(s) to produce a toxicokinetic interaction, and is likely to be reflected in the detoxification process by increasing or decreasing the toxic potential of a compound, as the amount of active molecular species also increases or decreases. Thus, whenever chemicals are associated during mixed exposure, the overall response, as far as the toxicity of individual chemicals is concerned, can be characterized in five ways (Klaassen, 1980; Ballantyne, 1985): 1) independent action implies that the toxicity of the two chemicals in a mixture is qualitatively and quantitatively similar to the effects produced when they are given separately; 2) additive effect refers to the simple summing of the toxicity of the two chemicals in a mixture; 3) antagonism designates reduced toxicity; 4) potentiation implies that a relatively inert chemical qualitatively enhances the toxicity of an already potentially toxic chemical; and 5) synergism refers to enhanced toxicity contributed by the in-


39

tcraction of both potentially toxic chemicals in a mixture. As a result of kinetic interference between chemicals, not only the toxicity, but also the amount of the parent compound and/or mctabolite(s) can be modified (c.g., alteration of metabolic outcomc). In fact due to the generally low concentrations encountered during mixed exposure, modifications in the amount of the parent compound and/or metabolite(s) are often observed, rather than modifications in toxicity usually seen with higher levels of exposure. Eventually such metabolic interferences can have serious implications for the assessment of multiple solvent exposure in the workplace. Therefore, evaluation of occupational health risk from multiple chemical exposure is very demanding and a rather poorly explored field. It is imperative and inevitable to take into account the consequences of chemical interactions in the occupational health practice.

Recently, biological monitoring has become widely accepted as a more accurate of occupational health risks due to chemical exposure because it somemore or less directly, assesses the internal dose of chemicals. Unfortunately, how, the use of the term biological monitoring is not very consistent. In this article, this term is used as defined by a joint seminar organized by the EEC, NIOSH, and OSHA (Berlin et al., 1984): &dquo;The measurement and assessment of agents or their metabolites either in tissues, secreta, excreta, expired air or any other combination of these to evaluate exposure and health risk, compared to- an appropriate reference.&dquo; This brief review is restricted to a discussion on the influence of mixed exposure on the biological monitoring of exposure to commonly used volatile organic solvents, and does not discuss such influences on biological effects. In recent years, the number of journal articles, books and conferences on biological monitoring have increased manifold (Baselt, 1980; Lauwerys, 1983; Aitio et al., 1984; Berlin et al., 1984; Notten et al., 1986; Foa et al., 1987). New literature reviews are, therefore, important to monitor the trends of current research and the state of knowledge in this field. Despite the plethora of pubmeasure

lished material, a critical examination of the literature indicates that the influence of multiple chemical exposure on biological monitoring is still a poorly explored field, as was already noted by Riihimaki in a review article published in 1984. This points towards the usefulness of addressing anew the implications.of mixed exposure to industrial solvents for the biological monitoring of exposure by identifying 1) the influence of the solvent interactions on the biological indices of chemical exposure, and 2) how the eventual modifying effects on biological indicators can be taken into account to facilitate the evaluation of health risks due to multiple solvent exposure. Moreover, the American Conference of Governmental and Industrial Hygienists (ACGIH, 1990) has recently identified &dquo;the control of biological measurements of exposure to mixture by BEIs (biological exposure indices)&dquo; as an important issue that should be addressed in establishing biological exposure indices, in the future. Special attention is paid to the study


40

of the better documented ethanol-solvent interactions. Furthermore, this study is an attempt to stimulate further research on biological monitoring of multiple chemical exposure.

’

INFLUENCE OF MULTIPLE SOLVENT EXPOSURE ON BIOLOGICAL INDICATORS

Studies enumerated on solvent-solvent interactions (Table 1) and ethanol-solvent interactions (Table 2), overall about 30 studies, shed light on some of the possible effects of solvent interactions on the biological parameters used for health risk evaluation through biological monitoring of exposure on one hand, and also on the large gaps in our knowledge on the other hand. The majority of studies in animals and humans (Table 1) indicate that simultaneous exposure to solvents (haloalkanes, ketones, aromatic solvents), when compared with exposure to each solvent taken individually, produces toxicokinetic

interaction, e.g., interaction that affects the metabolic outcome. Most likely, under the prevailing experimental conditions, as a result of the inhibition of metabolic biotransformation, these binary associations have produced modifications at the level of indices of biological monitoring usually in terms of: 1) diminution of urinary metabolite excretion, 2) increase in concentration of unchanged solvent in blood and exhaled air. Consequently, there is a great possibility of overestimation or underestimation of health risk due to chemical exposure, depending upon the parameter selected. Methylene chloride interaction with toluene and alcohols presents a noteworthy exception. A mixture of toluene, isopropanol or ethanol with methylene chloride inhibited the formation of carbon monoxide in animals, thereby, reducing the production of carboxyhemoglobin and methylene chloride toxicity (Ciuchta et al., 1979). Whereas, the same study did not find any effect in animals treated with a mixture of methylene chloride and methanol, in contrast, exposure of workers to the mixture resulted in an increased production of carboxyhemoglobin (Stewart and Hlake, 1976). In most cases, the mechanisms of toxicokinetic solvent interactions have not been thoroughly investigated although, as mentioned above, inhibition of metabolic biotransformation is a likely explanation. The question of dose-dependency is an important issue, but has very rarely been addressed. Animal studies clearly demonstrate, however, that the importance of metabolic alterations are related to the degree of exposure above certain threshold doses of each individual solvent (Ikeda and Hirayama, 1978; Sato and Nakajima, 1979). In humans, a recent study by Tardif et al. (1991) has shown that at exposure concentrations of toluene and xylene likely to be found in the workplace (40 to 95 ppm), there is also a threshold level above which metabolic

interaction is present.


41

TABLE 1

Influence of Solvent-Solvent Metabolic Interactions of Solvent Exposure

on

Biological


Parameters

42

TABLE 1 Influence of Solvent-Solvent Metabolic Interactions on of Solvent Exposure (cont.)

Biological


Parameters

43

TABLE 1 Influence of Solvent-Solvent Metabolic Interactions on of Solvent Exposure (cont.)

Biological

Parameters

1) Hippuric acid is a metabolite of toluene, styrene and ethylbenzene; mcthylhippuric acid is a metabolite of xylene; phenol is a metabolite of benzene; mandelic and phenylglyoxylic acids arc both metabolites of styrene and ethylbcnzene; trichlorates are metabolites of trichloroethylene, 1,1,1-trichloroethane or tetrachloroethylene ; o- and p-bromophenol are metabolites of bromobenzene; cyanide is a metabolite of acetonitrile.

Special emphasis is given to the question of ethanol-solvent interactions (Table 2) because of the widespread use of alcoholic beverages, either occasionally or habitually, by persons who may also be occupationally exposed to a variety of chemicals. Furthermore, apart from the occasional industrial use of ethanol, studies of ethanol-solvent interactions are always of theoretical interest so as to gain insight into solvent interactions. The importance of the duration of exposure is very well demonstrated by ethanol studies. The effects of ethanol on microsomal metabolism appear to be complex and depend on the concentration and mode of treatment. Acute administration of ethanol inhibits biotransformation of ’another compound in association, whereas, chronic ethanol treatment produces enzyme induction and accelerates biotransformation (Rubin and Lieber, 1968). Thus, metabolic consequences in one and the other case are completely opposite and so is the influence of either treatment on the indicators of biological monitoring. All the studies assembled in Table 2 that deal with human volunteers reveal that effects of acute ethanol-solvent interactions on biological indices are qualitatively and quantitatively similar in pattern to those produced by solventsolvent interactions (Table 1) in the sense that they result in inhibitory-like effects on metabolic transformation of one of the solvents. On the other hand, two of the animal studies cited involve chronic exposure and this leads to the induction of microsomal activity and acceleration of the biotransformation of benzene and

trichloroethylene (Nakajima et al., 1985, 1988). It is rather important to note that there is a paucity

of studies conducted on solvent-solvent and ethanol-solvent interactions, and the existing studies mostly deal with acute conditions of exposure. However, the available information, although scanty, reveals that the three biological indices (urinary metabolites,


44

TABLE 2 Influence of Ethanol-Solvent Metabolic Interactions

of Solvent

on

Biological Parameters

Exposure

1) Acetaldehyde is a metabolite of ethanol; trichlorates are metabolites of trichloroethylene; methylhippuric a metabolite of xylene; mandelic and phenylglyocylic acids are metabolites of styrene; 2-butanol is a

acid is

’

metabolite of methyl

ethyl

kctone.


45

blood concentration and expired air concentration) which are predominantly used for the evaluation of health risks due to chemical exposure (ACGIH, 1990) are significantly affected by solvent-solvent and ethanol-solvent interactions in both animals and humans.

DISCUSSION The various studies summarized in Tables 1 and 2 corroborate the fact that under certain situations of multiple chemical exposure, the kinetics of a chemical undergo important modifications. Under these conditions, the parameters of biological monitoring could be markedly affected to the point of altering the estimation of toxic risk due to multiple chemical exposure. Consequently, the reliability of toxicity risk evaluation based on the measurement of internal exposure becomes questionable. Yet, as is clearly evident from rare animal (Ikeda and Hirayama, 1979; Sato and Nakajima, 1978) and human (Tardif et al., 1991) studies, there are threshold dose levels under which metabolic alterations are

likely

not to occur.

When there is inhibition of the biotransformation of a solvent, the excretion of inactive urinary metabolite{s) .is diminished, thereby resulting in the underestimation of toxic risk. On the contrary, the toxic risk would be overestimated if the parameter of biological monitoring is the measurement of the blood concentration of unchanged and active solvent. Thus, it is evident that toxicokinetic interactions not only modify the parameters of biological surveillance but also alter the assessment of the importance of toxic risk. Moreover, the error in risk interpretation could be diametrically opposite based on the choice of biological indicator used in risk evaluation, whether it is an inactive urinary metabolite or the active parent compound in blood.

Hence, in situations of multiple solvent exposure, the principle of additivity of

biological indices cannot be readily accepted as is the case of exposure indices of environmental monitoring (ACGIH, 1990). In fact, the principle of additivity for environmental surveillance is applicable under very specific conditions which can permit the definition of adjusted limit values of exposure. In accordance with the hypothesis of additivity, the adjusted limit value represents a reliable index of toxic risk because it adequately reflects the degree of ambient contamination. It, however, remains to be established which biological indicator should be used for prudent monitoring of multiple chemical exposure in situations of one solvent interfering with the biotransformation of another substance. The choice of a marker for biological monitoring of exposure is, therefore, very crucial. As far as possible, the parameters to be determined should be selected according to the mechanism of toxicity of solvents. This implies that the measurement of potentially toxic or biologically active molecular species would be ,a reliable risk index. This molecular species could very well be the parent com-


46

pound and/or its metabolite(s). The validity of this parameter to detect toxicokinetic interactions of solvents is discussed in the following examples. Many organic solvents, like toluene, in their unchanged form are central nervous system depressants. In case of toluene exposure in combination with other solvents, there is often a diminution of urinary excretion of hippuric acid and augmentation of toluene concentration in blood and expired air. Under these conditions, measurement of toluene in blood or expired air could be a reliable indicator of actual degree of toluene exposure even under conditions of mixed exposure. Similarly, certain solvents exert toxicity after biotransformation to their metabolites, e.g., n-hexane is metabolized to a neurotoxic metabolite 2,5-hexanedione. In this case, the measurement of 2,5-hexanedione would be a reliable parameter for biological monitoring. It must, therefore, be emphasized that an in-depth knowledge of the mechanisms of toxicity and potentially toxic molecular species are indispensable prerequisites for developing an effective program of biological monitoring of multiple exposure. SUGGESTIONS FOR AN APPROACH TO THE EVALUATION OF HEALTH RISKS DUE TO MULTIPLE SOLVENT EXPOSURE No complete set of guidelines currently exists to safely assess the health risk caused by mixed chemical exposure. In this study it is suggested firstly that the measurement of a potentially toxic molecular species, parent compound and/or its metabolite(s), is of primary importance in the evaluation of the toxic risk due to multiple solvent exposure. Secondly, a strategy for the determination of parameters which can provide evidence of the existence of kinetic interactions during multiple chemical exposure would be very useful. Thus the parallel measurement of the parent compound and a biologically active/inactive metabolite would permit the rapid formulation of an hypothesis on the nature of the interaction and, consequently, assist in the interpretation of biological monitoring results. This approach is mechanistic in nature and would be an important element for in-depth analysis of the existent relationship between external exposure, internal dose and the intensity of toxic effects. When the solvents in a mixture have similar effects on human body, it is reasonable to assume in the first place that their influence on the parameters of biological surveillance of mixed exposure would be at least additive. Consequently, under such conditions, the interpretation of biological indices of exposure must be governed by establishing a limit value for mixed exposure as in the case of ambient monitoring (ACGIH, 1990). However, it should be emphasized that the studies listed in Tables 1 and 2 show that, during multiple exposure, there are usually toxicokinetic interactions. These interactions might modify the parameters of biological monitoring in such a manner that the principle of additivity could not be applied. Such possibility underlines the judgemental nature


47

of evaluation of health risk due to multiple chemical exposure. The assessment of health risk during mixed exposure might, therefore, rely upon the measurement of potentially toxic molecular species and the judgement of professionals. In this way the interpretation of biological monitoring results and, most of all, the assessment of toxic risk would be minimally affected.

CONCLUSIONS AND FOCUS ON FUTURE RESEARCH NEEDS As mentioned above, there is a paucity of studies on solvent interactions in animals and, even more so, in humans. Furthermore, the published studies are deficient with respect to the following: 1) there are virtually no studies consisting of more than two solvents, 2) the concentrations used are often not relevant to occupational exposure, and 3) there are very few studies involving chronic exposure. The studies do, however, adequately describe the toxicokinetic alterations in the biological indicators as a result of multiple solvent exposure. Parameters such as the concentration of unchanged solvent in blood and expired air and, especially, the concentration of urinary metabolite, which are predominantly employed in occupational health practices may be significantly modified so as to cause a misinterpretation of the biological monitoring results. It is, therefore, suggested that the measurement of potentially toxic molecular species, parent compound and/or its metabolite(s), would facilitate biological monitoring of multiple solvent exposure. This approach appears to be important for drawing better quantitative conclusions on the internal exposure to biologically active

chemicals. Research needs will be briefly discussed to indicate the contributions required to bridge the gaps in our knowledge regarding the assessment of health risk as a result of multiple solvent exposure. Firstly, research should be addressed to investigate and identify the association of chemicals which are likely to pose more problems of interaction in the workplace. The number of possible chemical associations among the chemicals present in a work environment is indeed unlimited. It is, therefore, suggested that the study of associations which present a hazard should be favored. Criteria for the identification and evaluation of such associations can be based on: 1) the frequency of occurrence of an association, 2) the number of workers exposed, and 3) the toxic potential of an association as well as the individual substances constituting a mixture. Various types of studies as cited earlier (Carpenter et al., 1975; Thompson, 1982; Gosselin et al., 1984) can contribute significantly to the identification of different problems of interactions in an association of chemicals.

Secondly, the study of such identified chemical associations on human volunteers, under precisely defined conditions, is fundamental to the characterization of the influence of mixed chemical exposure on indices of biological monitoring of exposure. Such studies, when ethically feasible and if properly conducted, would


48 answers on mechanisms of interaction, and the biological thereof under conditions closely related to occupational exposure. consequences Thirdly, research on the influence of multiple exposure in repeated exposure situations should also be a priority. Even now, all ~of the human studies on the influence of multiple exposure on biological monitoring are conducted under conditions of acute exposure. There is a pressing need for chronic exposure studies because long-term exposure might exert a definite effect on the absorption, distribution, metabolism and/or excretion of chemicals.

provide much-needed

much support has accrued for the use of physiologically based pharmacokinetic models in the occupational health practices (Droz and Fernandez, 1978; Fiserova-Bergerova et al., 1980; Borm and de Barbanson, 1988). This approach has not yet been exploited to study the implication of multiple chemical exposure for biological monitoring. The use of this model would be of vital importance in mixed chemical exposure studies to help define biochemical parameters characterizing the metabolic constants of tissues involved in biotransformation, extrapolate animal data to humans (scale up), and reduce the number of experimental studies actually required to provide evidence of the influence of multiple solvent exposure on the parameters of biological monitoring.

Recently,

fundamental research is needed to gain an in-depth knowledge of: 1) the nature of molecular species responsible for toxic effects, 2) mechanism of toxic action of various substances involved in multiple exposures, and 3) toxicokinetic or toxicodynamic mechanisms responsible for the interactions observed during multiple exposures.

Finally,

ACKNOWLEDGMENT The authors acknowledge the financial support of IRSST (Institut de recherche en sant6 et en securite du travail du Qudbec) for the preparation of a report on &dquo;The assessment of occupational health risk from multiple exposure.&dquo; Core financial support to Research Group in Industrial Toxicology at Universit6 de Montr6al is also acknowledged. The authors wish to thank Mrs. E. Orphanos for the preparation of this manuscript.

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Biological monitoring for occupational exposure to toluene.

Biological monitoring of occupational exposure to tetrahydrofuran.

Biological and chemical monitoring of occupational exposure to ethylene oxide.

Biological monitoring for occupational cadmium exposure: the urinary metallothionein.

Occupational chronic exposure to metals. II. Nickel exposure of stainless steel welders--biological monitoring.

Organic brain damage and occupational solvent exposure.

Occupational Exposure to Mercury: Air Exposure Assessment and Biological Monitoring based on Dispersive Ionic Liquid-Liquid Microextraction.

Risk assessment of leukaemia and occupational exposure to benzene.

A non-invasive monitoring of exposure to an industrial organic solvent, dimethylformamide.

Urinalysis vs. blood analysis, as a tool for biological monitoring of solvent exposure.

Exposure monitoring and risk assessment of biphenyl in the workplace.

Breast cancer risk after occupational solvent exposure: the influence of timing and setting.

Biological monitoring, by in vivo XRF measurements, of occupational exposure to lead, cadmium, and mercury.

Biological monitoring of exposure to nerve agents.

Estimating occupational beryllium exposure from compliance monitoring data.

Biological monitoring of human exposure to acephate.

Grey-scale ultrasonography for monitoring industrial exposure to hepatotoxic agents.

Biological monitoring of bidi rollers with respect to genotoxic hazards of occupational tobacco exposure.

Exposure Estimation and Interpretation of Occupational Risk: Enhanced Information for the Occupational Risk Manager.

A current review for biological monitoring of manganese with exposure, susceptibility, and response biomarkers.

A systematic review of the physical health impacts from non-occupational exposure to wildfire smoke.

Occupational exposure to pesticides and respiratory health.

Development of risk-based nanomaterial groups for occupational exposure control.

Occupational exposure and ovarian cancer risk.