Document Eo4YzgYvo3ee3Vovkbbyw8DR

,H> U ]> SiQdlGSlb FILE: --* K-2525-(100) fl986lr K-1712- ' K-2511- 'H K-2516- K-1985K-1711- \ K-2520- K-2521- K-1716- \ ' W-V/ %'.-/ft*- . . Conference on Medical Screening and Biological Monitoring for the Effects of Exposure in the Workplace Biological Monitoring of Chlorinated Hydrocarbon Solvents Aart C. Monster, PhD 3D fio (A o to >4 The possibility of biological monitoring of exposure to some nonflammable and liposoluble. Table 2 lists the solvents, volatile, halogenated hydrocarbons will be discussed. Most of these agents are widely used as solvents. All agents act on the nervous system as narcotics and differ widely in toxicity. Most the formula, the metabolites, and the possibilities for biological monitoring. of the solvents undergo biotransformation to metabolites. This allows biological assessment of exposure by measurement of the solvent and/or metabolites in exhaled air, blood, and/or Solvents urine. However, the same metabolites may occur with expo sure to different chlorinated hydrocarbons, eg, trichioroe- Monochloromethane (methyl chloride) is used as a I thanol and trichloroacetic acid from exposure to trichloroethene, tetrachlcroethene, and 1,1.1-trichloroethane, On the other blowing agent for plastic foam and as a chemical inter mediate in methylation reactions. It is a gas at room hand, these agents differ widely In the percentage that is temperature, colorless, and its odor is not detectable at metabolized. There are large gaps in our knowledge, however, and much research will have to be carried out before even tentative data can be established for most of the solvents. concentrations in air that may already be injurious to health. The nervous system appears to be the critical target organ. The symptoms may occur after a latency time of several hours. This roview of the possibilities for the biological mon itoring of exposure to volatile halogenated hydro Van Doom et al" identified S-methylcysteino in urine as a metabolite for almost all the retained methyl chlo carbons is mainly based on the monograph to the Com ride in four out of six workers; the other two workers mission of the European Communities, prepared by excreted less than 10%. Monster and Zielhuis.' Considerable data concerning Stewart et al3 and Putz-Anderson et al4 also distin the biological monitoring of volatile halogenated hydro guished two groups: the majority had methyl chloride carbons have been published internationally. Neverthe concentrations in blood and breath that were two to six less, the difference in approach to research, the variety times lower than in the minority. These findings of analytical methods, and the frequent discordances in results usually make it difficult to make proposals for strongly suggest the existence of two populations: a minority of poor converters with a high body burden of biological monitoring. methyl chloride and a majority of "converters" with a Table 1 lists the halogenated hydrocarbon solvents lower methyl chloride body burden. It is not clear that will be discussed. These solvents differ widely in whether this difference in metabolism indicates a differ toxicity and in their TLVs. All solvents are more or less ence in susceptibility to methyl chloride. However, how can the different types of subjects be distinguished? The probable answer is by measuring the solvent in blood or exhaled air as well as by measuring From th* University of Amsterdam. Coronal Laboratory (Dr Mona tor. Faculty of Meaicino). Addrou correspondence to: Coronsl Laboratory, Faculty of Medicino. University of Am*tordam. Melbargdraof 16, 1 lGf A2 Amsterdam. S-mcthylcysteine in urine. Dichloroatethame (methylene chloride) is the least toxic of the four chlorinated methanes. Dicbloromethane is used as a blowing agent for foams and as solvent for The Netherlands (Dr Monstar). many applications. Dichloromethane also has well- ooon-1738/86/0806-603*00-00/0 Copyright by American Occupational Medical Auociatlon known narcotic effects and is slightly irritating to mu cous membranes end skin. Journal of Occupational Medicine/Volume 28 No. 8/Augu$t 1986 583 The increased concentration of carbon monoxide (CO) after exposure to dichloromethane was first observed by Stewart and co-workers in 1972." Such symptoms of carbon monoxide poisoning as headaches, however, have not been a common feature of dichloromethane expo sure. Approximately 25% of the dichloromethane ab sorbed is ultimately excreted as CO and the postexpo sure excretion of dichloromethane by exhalation is less than 5% of the amount absorbed.8 From the human volunteer studies of Stewart et al,7 DiVincenzo et al,8 and related studies, several conclu sions concerning exposure to dichloromethane may be drawn. Pulmonary uptake is rapid and remains essen tially unchanged after the first hour. Interruption of the exposure causes a rapid die-away curve. The reten tion (R) seems to decrease in relation to the increasing concentration of exposure, ie, the relative uptake de creases and the relative concentration in blood increases V.- H1CL -iviASlL ml v,-nit, - TABLE 1 Haiogenated Hydrocarbon Solvents and Their TLVs Solvent T'.V (Pf-m) 1984/1985 (mg/m1) .. Monochiorcmethane. Dichloromethane . .Trichloromethane Tetrachloromelhane. -1,2'DichiorQethane^ Monochloroethene _Trichjoroethene Tetrachloroethene 1,1,1-Trichloroethane 50 100 10 5 10 5 50 50 350 105 350 50 30 40. 10 270 335 non when the exposure concentration is increased. When the exposure concentration is increased, the concentra tions in exhaled air in the postexposure period are not only absolutely higher, but also relative. The decreasing retention (R) during exposure and the relative increas ing concentrations in the postexposure period with increasing exposure concentrations are possible indica tions that the metabolism is saturable not only in ani mals but also in human subjects. The half-life of dichlo romethane in the postexposure period depends on the length of exposure and the time of sampling. The con centration in exhalod air more or less follows the con centration in blood. The ratio between the concentration of solvent in blood and the concentration in exhaled air depends on the solubility of the solvent in blood. Female subjects have about the same concentration in blood as male subjects during the first hours after exposure. Sixteen hours after exposure however, women tond to have higher concentrations in exhaled air.7 This differ ence could be due to a higher amount of fatty tissue in women. Engstrom and Bjurstrom8 found that, during tho first two hours after exposure, tho concentration in alveolar air tended to be lower and declined more rapidly in obese subjects than in slim ones. After this, the concen tration dropped more slowly in the obese group. During the later phase of elimination, the obese subjects tended to have a higher concentration in alveolar air. Astrand et al* reported that the amount of dichloro methane taken up increased with physical work load, whereas tho retention decreased. With 50-watt work TABLE 2 Hatogenated Hydrocarbon Solvents Formula, Metabolites, and Possibilities lor Biological Monitoring Name Formula Metabolite Biological Monitoring Monochioromethane CHjCI S-Mcthylcysteine Monochioromethane (?) S-methylcysteine (?) Dichloromethane CHjCIj Carbon monoxide Dichloromethane Carbon monoxide Trichloromethane CHCb Tnchloromethanol 0 Phosgene (?) 2-Oxothiazolidme carboxylic acid N-(2-Oxothiazc:idine- 4-carboxyl)-glvcine Trichloromethane 2*oxothiazoiadine-4- carboxylic acid (?) Tetrachloromethane CCL Trichloromethane (?) Hexachlorocthane 0 Tetrachloromethane (?) 1,2-Dichloroethane Monochloroethene Trichloroethene Tetrachtoroethene 1.1.1 -Tnchioroethane HjClC-- ch2ci HjC--CHCI CbOrCHCI CljC--CCI2 HjC--CCI3 2-Chloroethanol Monochloroacetic acid Chioroacetaidehyde Monochloroacetic acid Tnchloroethanol Trichloroacetic acid Trichloroacetic acid Tnchloroethanol (?) Trichloroethanol Trichloroacetic acid 1,2-Dichloroethane (?) Monochloroacetic acid (?) Thiodiacetic acid 0 Monochloroethene (?) Monociilcroacetic acid Thiodiacetic acid Tnchloroethanol Trichloroacetic acid Trichloroethene Trichloroacetic acid Tetrachtoroethene Tnchloroethanol (?) Tnchloroethanol Trichloroacetic add 1,1.1 -Tnchloroethane S84 Chlorinated Hydrocarbon Solvents/Monster 73 B* (/) IO -C* IO iu j..- load, the uptake was twice as high, whereas the reten tion decreased from 66% to 46%. When exposure was coupled with physical work load, the concentration in alveolar air was increased during the whole postexpo sure period compared with exposure under rest condi tion*-9 DiVincenzo and Kaplan10 reported similar re sults. They showed that exercise was accompanied by increased pulmonary excretion of carbon monoxide dur ing exposure, which undoubtedly contributed to the lower than expected carboxyhemoglobin (COHb) values encountered during heavy work loads. Engstrom and Ejurstrom8 measured the concentra tion of dichloromethane in subcutaneous adipose tissue after exposure (760 ppm, one hour, 60-watt work load). In six slim subjects, the concentration four hours after exposure was on average twice that in six obese sub jects. On the other hand, the obese subjects had greater calculated amounts of dichloromethane in the total fat depots in their bodies. More studies will have to be carried out to provide data on concentrations in adipose tissue in relation to various exposure levels. Compared with the concentration of dichoromethane in alveolar air, the concentrations of carbon monoxide and carboxyhemoglobin increase and decrease slowly; interruption of the exposure (during lunch and after exposure) cause either a slow die-away curve or none at all.0 The maximum COHb is sometimes reached zero to two hours after exposure. The biological half-life of COHb after exposure to dichloromethane is about 12 to 16 hours, ie, double the half-life of COHb levels after CO exposure. This can be explained by the continuous for mation of carbon monoxido from dichloromethane after exposure. There are indications that simultaneous ex posure to other solvents may increase the biological half-life of COHb. The combined effect of smoking and exposure to dichloromethane produces an additive in crease in blood carboxyhemoglobin levels.10 Biological monitoring of dichloromethane exposure can be based on measurement of the solvent itself in exhaled air or blood. However, as production of CO with exposure for more than three to four hours per day appears to be the limiting factor in regard to health risk, biological monitoring based upon either analysis of CO in exhaled air or of COHb in blood is to be preferred. This can only be applied in nonsmoking subjects. Sam pling should be done about zero to two hours after exposure or after 16 hours on the following morning. Trichloromethane (chloroform) once was widely used as an anesthetic. Because of often-delayed liver injury, this use is now considered absolute. There is also con siderable evidence that chloroform is carcinogenic m mice and rats. Few data exist on chloroform metabolism in healthy workers; most data refer to studies in anesthetized patients. At least a part of the chloroform is metabolized to carbon dioxide, and another part is exhaled un changed; the formation of trichloromethanol phosgene, 2-oxothiazolidine-4-carboxylic acid (OTZ) and N-(2-oxothiazolidine-4-carboxyl)-glycine (OTZG) is also as sumed.11 The reaction of phosgene with tissue molecules is believed to produce liver and kidney damage. Up to now, no metabolite has been identified in the blood ormrine that could be considered useful in evalu ating occupational exposure to chloroform. Tetraohtoromethane (carbon tetrachloride) is being used less because of awareness of the hepatotoxicity and the availability of less hazardous solvents. The evidence is sufficient to show that carbon tetrachloride is carcin ogenic in experimental animals. Liver and renal function tests are regarded as the most sensitive and practical methods of detecting early health impairment.19 In acute exposure, both live* and kidney function may be most critical; in chronic expo sure, liver effects are predominant. Only a few studies on metabolism exis*. The formation of CCl3-radicals is assumed to be the initial step in biotransformation. The radicals subsequently bind ir reversibly to cellular macromolecules and initiate lipid peroxidation. Fart is excreted unchanged and another part as COg. The formation of the radicals is supported indirectly by the appearance of small amounts of chlo oform and hexachloroethane in tissue of rabbits after administration of tetrachloromet'nane.13 It is vory probable that measurement of carbon totrachlo.ide in exhaled air or blood will be the method of choice for biological monitoring. However, few data exist. 1,2-Dichloroethane (ethylene dichloride) is used as a starting material for vinyl chloride; it is also used as an antiknock agent in gasoline and as a solvent. At very high concentrations, 1,2-dichloroethane is irritating to the eyes, nose, and throat. Exposure may also affect the CNS, liver, kidneys, and skin. A specific critical target organ has not been identified. There is sufficient evi dence that 1.2-dichloroethane is carcinogenic in mice and rats. The nature of the metabolism of 1,2-dichloroethane has not been established, but some appears to go through 2-chloroethanol to monochloroacetic acid and further to oxalic acid: however, S-carboxymethylcysteine and thiodiacetic acid have also been detected.14 However vinylchloride gives the same metabolites. No references have been found that would indicate satisfactory biological monitoring for industrial hygiene contrcl. Among the possible methods are measurement of dichloroethane in blood and exhaled air or measure ment of its metabolites in blood and urine. Modochioroethene (vinyl chloride) is used as a mon omer in polyvinylchloride (PVC) production. Many stud ies in workers have shown that vinyl chloride is a human carcinogen. Up to about IS years ago, vinyl chloride was regarded as rather harmless, so little effort was devoted to study ing its metabolism. Currently, it is thought that vinyl chloride is metab olized by epoxidation with subsequent production of chloroacetaldehyde. Further oxidation and conjugation with glut&thion are responsible for the metabolites found in the urine, such as s-arboxymethylcysteine and thiodiacetic acid.13'10 No valid routine biological moni toring method exists to evaluate vinyl chloride exposure at present-day accepted levels. Increased urinary ex cretion of metabolites such as thiodiacetic acid promises Journal of Occupational Medicine/Volume 28 No. 8/August 1986 585 V;'33?r^MiPr^'*l*^,P*<iW* JVU.T^JSCui'i-fT'in ""^SmS338 load, the uptake was twice aa high, whereas the reten tion decreased from 65% to 45%. When exposure was coupled with physical work load, the concentration in alveolar air was increased during the whole postexposure period compared with exposure under rest condi tions,* DiVincenzo aril Kaplan10 reported similar re sults- They showed that exercise was accompanied by increased pulmonary excretion of carbon monoxide dur ing exposure, which undoubtedly contributed to the lower than expected carboxyhemoglobin (COHb) values encountered during heavy work loads. Engstrom and Ejurstrom8 measured the concentra tion of dichloromethane in subcutaneous adipose tissue after exposure (750 ppm, one hour. 50-watt work load). In six slim subjects, the concentration four hours after exposure was on average twice that in six obese sub jects. On the other hand, the obese subjects had greater calculated amounts of dichloromethane in the total fat depots in their bodies. More studies will have to be carried out to provide data on concentrations in adipose tissue in relation to various exposure levels. Compared with the concentration of dietioromethano in alveolar air, the concentrations of carbon monoxide and carboxyhemoglobin increase and decrease slowly; interruption of the exposure (during lunch and after exposure) cause either a slow die-away curve or none at all.8 The maximum COHb is sometimes reached zero to two hours after exposure. The biological half-life of COHb after exposure to dichloromethane is about 12 to 16 hours, in, double the half-life of COHb levels after CO exposure. This can be explained by the continuous for mation of carbon monoxide from dichloromethane after exposure. There are indications that simultaneous ex posure to other solvents may increase the biological half-life of COHb, The combined effect of smoking and exposure to dichloromethane produces an additive in crease in blood carboxyhemoglobin levels.10 Biological monitoring of dichloromethane exposure can be based on measurement of the solvent itself in exhaled air or blood. However, as production of CO with exposure for more than three to four'hours per day appears to be the limiting factor in regard to health risk, biological monitoring based upon either analysis of CO in exhaled air or of COHb in blood is to be preferred. This can only be applied in nonsmoking subjects. Sam pling should be done about zero to two hours after exposure or after 16 hours on the following morning. Trichloramethaae (chloroform) once was widely used as an anesthetic. Because of often-delayed liver injury, this use is now considered absolute. There is also con siderable evidence that chloroform is carcinogenic ;n mice and rats. Few data exist on chloroform metabolism in healthy workers; most data refer to studies in anesthetized patients. At least a part of the chloroform is metabolized to carbon dioxide, and another part is exhaled un changed; the formation of trichloromethanol phosgene, 2-oxothiazolidine-4-carboxylic acid (OTZ) and N-(2-oxothiazolidine-4-carboxyl)-glycine (OTZG) is also as sumed.11 The reaction of phosgene with tissue molecules is bolieved to produce liver and kidney damage. Up to now, no metabolite has been identified in the blood or urine that could be considered useful in evalu ating occupational exposure to chloroform. Tetrznhloromethane (carbon tetrachloride) is being used less because of awareness of the hepatotoxicity and the availability of less hazardous solvents. The evidence is sufficin', to show that carbon tetrachloride is carcin ogenic in experimental animals. Liver and renal function tests are regarded as the most sensitive and practical methods of detecting early health impairment.11 In acute exposure, both live; and kidney function may be most critical; in chronic expo sure, liver effects are predominant. Only a few studies on metabolism exisV The formation of CCl3-radicals is assumed to be the initial step in biotransformation. The radicals subsequently bind ir reversibly to cellular macromolecules and initiate lipid peroxidation. Fart is excreted unchanged and another part as COs, The formation of the radicals is supported indirectly by the appearance of small amounts of chlo oform and hexachloroethane in tissue of rabbits after administration of tetrachloromethane.18 It is very probable that measurement of carbon tet rachloride in exhaled air or blood will be the method of choice for biological monitoring. However, few data exist. 1,2~Dichloroethane (ethylene dichloride) is used as a starting material for vinyl chloride; it is also used as an antiknock agent in gasoline and as a solvent. At very high concentrations, 1,2-dichloroethane is irritating to the eyes, nose, and throat. Exposure may also affect the CNS, liver, kidneys, and skin. A specific critical target organ has not been identified. There is sufficient evi dence that 1,2-dichloroethane is carcinogenic in mice and rats. The nature of the metabolism of 1,2-dichloroe thane has not been established, but some appears to go through 2-chloroethanol to monochloroacetic acid and further to oxalic acid; however, S-carboxymethylcysteine and thiodiacetic acid have also been detected.18 However vinylchloride gives the same metabolites. No references have been found that would indicate satisfactory biological monitoring for industrial hygiene control. Among the possible methods are measurement of dichloroethane in blood and exhaled air or measure ment of its metabolites in blood and urine. Moaochioroethene (vinyl chloride) is used as a mon omer in polyvinylchloride (PVC) production. Many stud ies in workers have shown that vinyl chloride is a human carcinogen. Up to about 15 years ago, vinyl chloride was regarded as rather harmless, so little effort was devoted to study ing its metabolism. Currently, it is thought that vinyl chloride is metab olized by epoxidation with subsequent production of chloroacetaldehyde. Further oxidation and conjugation with glutathion are responsible for the metabolites found in the urine, such as s-arboxymetbylcysteine and thiodiacetic acid.15'18 No valid routine biological moni toring method exists to evaluate vinyl chloride exposure at present-day accepted levels. Increased urinary ex cretion of metabolites such as thiodiacetic acid promises Journal of Occupational Medicine/Volume 28 No. 8/August 1986 585 > 92471s distribution, metabolism, and excretion of perchloroethylene. FEE is almost totally excreted by exhalation. Only a small amount of the PER that is absorbed in the body is metabolized to trichloroacetic acid (2%) and excreted in urine."'** FEE has a long: half-life when measured in expired sir or blood, probably because of deposition in fat and similar tissue. It has a half-life of approximately four to six days in short-term experiments and approximately six to eight days in long-term exposure (workers in dry cleaning shops). The blood/air and fat/air partition coefficients of PEE at 37*C are about 15 and 2,000, respectively."'*7 In cases of exposure to PER, the concentration of TCA in blood and urine is much lower than after exposure to TEI, but the kinetic behavior of TCA is more or less the same. Work load during exposure increases the blood, and exhaled air concentrations not only during expo sure, but also in the postexposure period. Alcohol con sumption during exposure has no effect on the concen tration of PEE either during or after exposure. Repeated exposure experiments indicate that PER accumulates in the body; therefore, PER In alveolar air and In blood in the first hour after exposure is probably more indicative of a TWA concentration than of a recent concentration; the concentration on the following morn ing and after the weekend probably indicates the TWA exposure during the preceding days or weeks. For TCA in blood and urine, the time of sampling is not important; it indicates the TWA exposure during the preceding week(s). In contrast to the experiments, small amounts of trichloroethanol (TCE) were found in the urine of work ers in Industrial studies."'* Japanese studies indicate that the capacity of humans to metabolize PER above 100 ppm is limited.*0'1 In addition, they find much higher values for TCE and TCA In urine. This difference may be at least partly explained by the difference in analysis. They used a nonspecific spectrophotometric method: a modified Fujlwara reaction. Monster et al" investigated exposure to PER in drycleaning shops during the entire woik" week. Blood, alveolar air, and urine were sampled on several days of the work week. Table 4 shows the estimated concentra tions in the biological specimena in a daily TWA expo- TABLE 4 Mean Concentrations o( Tetrachkxoethene (PER). Trichloroethanol (TCE), ana Trichloroacetic add (TCA) in Blood, Alveolar Air. and/or Urns in Subjects Exposed to a TWA Exposure ol SO ppm (345 mg/m1) PER 8 h/d. 5 d/wk' Time ol Sampling Attar Exposure End ol Expaaura 5-15 min 64 It Blood (mg/L) PER TCE TCA Alveolar air (PER) mg/m5 ppm Lkine (mg/g creatinine) TCA TCE 9.7 0.5 2.3 0.82 ---- 5.8 3.8 160 53 23 8 4.9 -- TABLE 5 Mean Concentrations ol l.l.l-Tricntoroethane(MC), Trichloroethanol. (TCE) and Trichloroacetic Acid (TCA) m Blood. Alveolar Ax, and Urine in Subjects Exposed to a TWA Concentration ol 50 ppm (275 mg/m1) ol MC 6 h/d. 5 d/ wk' Tima ol Sampling Altar Exposure Test End of Expour* 5-15 min 15 h 64 h Blood (mg/L) f MC 0.9 0.07 TCE 0.16 -- TCA 2.3 1.6 Alveolar air MC. mg/m1 (ppm) 210(39) 13(2.4) 8(1.5) TCE mg/m5 0.014 0.007 -- Urine (ma/a creatinine) TCA 4.9 2.5 0.9 TCE 2.5 1.8 1.5 sure to 50 ppm.1 The results also indicate that PER in blood after work on Friday seemed to be the best param eter for estimating.the TWA-week exposure. For PER in alveolar air and TCA in urine and blood, the spread was somewhat larger. TCE was more related to the TWA exposure during two preceding days than to the TWA exposure during the week or during one day. The data published for biological monitoring of PER are limited in scope and not yet sufficiently validated, but they are very promising. Because PER (and TCA) appear to accumulate in the body, adequately controlled observations in industry in workers exposed for at least a few weeks are needed to establish valid biological monitoring parameters. 1,1,1-Trichloroethane (methylohloroform [MC]) is widely used os a solvent. The principal and first response is depression of the CNS. The low toxicity appears to be related to the low solubility in blood and adipose tissue (X blood/air: 3 to 6, X fat/air: 360)"'*7 and the small amount of metabolism that occurs. MC is almost totally excreted by exhalation, whereas only small amounts of TCE (2-5%) and TCA (1% to 2%) are excreted in urine.32'33 The kinetic behavior of TCE and TCA is more or less the same as after exposure to TRI or PER. Work load during exposure to MC increases Its concentration in alveolar air during the whole postexposure period.33 Monster34 investigated exposure to MC in four work shops. During an entirely normal work week, exposure to MC was measured with personal air samplers. Blood, alveolar air, and urine were sampled on several days of the work week. Table 5 shows the estimated concentra tion at the end of the work week after daily exposuro to 50 ppm MC. The concentrations of TCE and TCA in urine are somewhat lower than those found by Seki et al36 and Tada.3* This can partly be explained by differ ences in analysis: Seki et al and Tada used the nonspe cific spectrophotometric Fujiwara reaction. The results also indicated that TCA in blood after work on Friday seemed to be the best parameter for estimation of the TWA-week exposure. TCA was followed by MC in ex haled air the next Monday. The combination of two parameters measured at the same time resulted in a somewhat smaller SD than for single parameters. The best combinations were MC and TCA in blood on Friday Journal of Occupational Medicine/Volume 28 No. 8/August 1986 587 R&S 024716 evening and the following Monday, but the combination of TCE and TCA in urine on Friday'was also reasonably satisfactory. For one-day exposure, the smallest SD was obtained for TCE in blood and urine. The reliability of the esti mation increased, however, when estimation of the TWA exposure was calculated for the previous two days in stead of one day. The best method to use for estimation of exposure to MC depends on the nature of the inves tigation: long-term exposure: TCA and MC; short-term exposure; MC (directly after exposure); one (two) day(s) exposure: TCE. Also in the case of MC, more data, particularly from repeated exposure studies and from studies in industry, should be available before an adequate proposal for biological monitoring can be presented. Conclusion There are still large gaps in our knowledge, and much research will have to be carried out before evon tenta tive data can be established for most of the solvents. Only for the solvents trichloroethene, tetrachloroethene, 1,1,1-trichloroethane, and to a lesser extent, dichloromethane are the relations between environmental mon itoring more or less available, and they are available only as group average values. References 1. Monster AC, Zielhuls RL; Chlorinated hydrocarbon solvenu, in Alessio L, Berlin A. Rol R, et al (eds): Human Biological Monitoring of Industrial Chemical Sorias. Luxembourg, Commission of European Communities 1983, pp 45-104. 2. van Doom R, Borm PJA, Leijdekkor CM, et al; Detection and identification of S-methylcysteine in urine of workers exposed to methyl chloride. Int Arch Occup Environ Health 1980.46:99 -109. 3. Stewart RD, Hake CL. Wu A. et al; Methyl Chloride: Develop ment of a Biological Standard for the Industrial Worker by Breath Analysis. Milwaukee, Modlcal College of Wisconsin, 1977. 4. Putz-Anderson V, Setzor JV, Croxton J$. et al: Methyl chloride and diazepam effect* on performance. Scand J Work Environ Health ,1981;7:8-13, 6 Stewart RD, Fisher TN, Hoska MJ, et al: Experimental human exposure to methylene chloride. Arch Environ Health 1972:25:342348. 8. DiVincenzo QD, Kaplan CJ: Uptake, metabolism and elimination of methylene vapor by humans. Toxicol Appl Pharmacol 1981:59:130140. 7, Stewart RD, Hake CL, Wu A: Use of breath analysis to monitor methylene chloride exposure. Scand J Work Environ Health 1976;2:57-70. 8, Engstrom J, Bjurstrom R: Exposure to methylene chloride, content in subcutaneous adipose tissue. Scand J Work Environ Health 1977;3:215-224. 9, Astrand I, Ovrum P. Carlsson A: Exposure to methylene chlo ride: 1. Its concentration in alveolar air and blood during rest and exorcise and it* metabolism. Scand J Work Environ Health 1975:1:7894. 10. DiVincenzo QD, Kaplan CJ; Effect of exercise or smoking on the uptake, metabolism and excretion of methylene chloride vapor. Toxicol Appl Pharmacol 1961;59:141-148. 11. Branch Lower RV, Nunn DS. Highet RJ. et al.: Nephrotoxicity of chloroform: metabolism to phosgene by the mouse kidney. Toxicol Appl Pharmacol 1984. 12. Early detection of health impairment in occupational exposure to health hazards. Organic solvents; Benzene, carbon t**rachloride. ketones, trichloroethylene, xylene. Metals: Cadmium, lead, manganese, mercury. Report of WHO meetings. Geneva, World Health Organize* lion, 1979. 13. Fowler JSL; Carbon tetrachloride metabolism in the rabbit. Bnt J Pharmacol 1969;37:733-737. 14. Yllner S: Metabolism of 1,2-dlchloroethane-,4C in mouse. Acts Pharmacol Toxicol 1971:30:257-265. 15. Veinio H: Vinyl chloride and vlnylbeozene (styrene)-metabolism, mutagenicity and carcinogenicity. Chain Biol Intersect 1978;22:117-124. 16. Muller 0, Norpoth K. Kusters E, et al; Determination of thiodigiycoiic acid in unne specimens of vinyl chloride exposed work ers. Int Arch Occup Environ Health 1978;41:119-205. 17. Fernandez JO, Droz PQ. Humbert BE, et al; Trichloroethylene exposure. Simulation of uptake, excretion and metabolism using a mathematic model- Br J Ind Med 1977;34:43-55. 18. Monster AC. Boersma G. Duba WO: Pharmacokinetics of tri chloroethylene in volunteers. Influence of workload and expoeure concentration. Int Arch Occup Environ Health 1976;38:87-102. 19. Monster AC. Boersma G, Duba WC: Kinetics of trichloroethyi* cne in repeated exposure of volunteer*. Int Arch Occup Environ Health 1979;42:283-292. 20. Muller G. Sp&ssovski M. Henschler D: Metabolism of trichlo roethylene in man: 111. Interaction of trichloroethylene and ethanol. Arch Toxicol 1975;33:173-189. 21. Stewart RD, Hake CL, Le Brun AJ. et al: Biological Standards for the Industrial Workers by Breath Analysis: Trichloroethylene. US Dept of Health, Education and Welfare, Cincinnati, 1974. 22. Droz PO, Fernandez JG: Trichloroethylene exposure. Biological monitoring by breath and urine. Br J Ind Med 1976;35:35-42. 23. Fernandez J, Guberan E, Caperos J: Experimental human exposures to tetrachloroethylene vapor and elimination in breath after inhalation. Am Ind Hyg Assoc J 1970:37:143-150. 24. Hake CL, Stewart RD: Human exposure to tetrachloroethylene, inhalation and skin contact. Environ Health Perspect 1977:21:231- 238. 25. Monster AC, Boersma G, Steenweg H: Kinetics of telrachloro- othylcno in volunteers: Influence of exposure concentrations and work load. Int Arch Occup Environ Health 1979;42:303-309. 26. Droz PO, Fernandez J: Solubility of organic solvents: 1, Go* chromatographic determination of olive oil-gas partition coefficient*. Helv Chim Acta 1977;60:454-458. 27. Sato A. Nakajima T; A structure-activity relationship of some chlorinated hydrocarbons. Arch Environ Health 1979:34:69-75. 28. Monster AC, Regouin-Peeter* W. Van Schijndel A. et al: Bio logical monitoring of occupational exposure to tetrachloroethene. Scand J Work Environ Health 1983;9:273-281, 29. Weichardt H, Llndnor J; Gesundheitsgefahren durch Ferchlorathylen in Chemisch-Reinigungsbetrieben aus arbetismedizinisch-toxikolo-gischer Sicht. Stauh-Reinhalt Lu/t 1975;35:416-420. 30. Ikeda M. Ohtsuji H. Imamura T. et al: Urinary excretion of total trichloro-compounds. trichioroethanol- and trichloroacetic acid a* a measure of exposure to trichloroethylene and tetrachloroethylene. Br J Ind Med 1972;29:328-333. 31. Ohtsuki T. Sato K, Koizumi A, et al; Limited capacity of human* to metabolize tetrachloroethylene. Int Arch Occup Environ Health 1083;51:381-390. 32. Humbert BE, Fernandez J: Exposure to 1,1.1-trichloroethane: study of it* absorption, excretion and metabolism in humans. Arch Mai Pm/1977:38:415^425. 33. Monster AC, Boersman G. 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