Assessment of concentration peaks in setting exposure limits for air contaminants at workplaces, with special emphasis on narcotic and irritative gases and vapors.

In various countries, concentration peaks of gaseous air contamination are assessed by a standard formula. Toxicologic data are not sufficient to warrant occupational short-term exposure limits for the majority of substances. In this article the literature on exposure to concentration peaks is reviewed, and the problem is analyzed from general toxicokinetic and physicochemical points of view. Several ways are suggested to achieve better standards. One straightforward and reasonably simple method is summarized in the following three points, which should be considered in the setting of occupational exposure limits: (i) For substances with fast or moderately fast action, only ceiling limits should be considered; (ii) when structure analogy is justified for narcotic and irritating gases, the correct way is to set the limits at the same thermodynamic activity (relative saturation) of the substances in question and not at the same concentration; (iii) for substances absorbed and eliminated slowly time-weighted exposure limits, combined with rules for excursions, or short-term exposure limits derived from such rules are appropriate, but the possible accumulation of large absolute quantities of the substances should be considered. This point is particularly important when the critical effect is narcosis or irritation, as the thermodynamic equipotency means that the effective concentration of water-soluble gases and vapors is higher than that of substances with low water solubility.


Models of toxicologic effects
Atherley (7) showed that the concept of the timeweighted average (TWA), as a basis for setting limit values, implies that the toxic effects are proportional to CT = k, ie, the product of the exposure concentration (C) and the exposure time (7), where k for a given effect is a constant, this being known as Haber's rule.
In contrast to this concept, it was early shown for a number of hydrocarbons, which typically have a fast to moderately fast rate of elimination, that, if the concentration in air declines, a more than proportional increase in exposure time is required to produce the same narcotic effect. Experimental data for these hydrocarbons better fit the model CP = k, where b is a constant that varies with the substance. Haber's rule is therefore applicable only to substances exhibiting slow elimination. where k is the elimination constant, which can also be expressed as a function of the half-time (Ty,) : k = (In 2)/Ty, . The value of k is calculated from the partition coefficient and the values, assumed for man , of the alveolar lung ventilation (eg, 360 IIh), the cardiac output of the heart (eg, 300 IIh), and the distribution volume for the substance in the body (eg, 70 I), cor responding to the bo dy volume of an average man, a reasonable assumption in this case (32). On the assumptions given, the biological half-time of the substance will be T y, = 0.135 (S + 1.2) h. A simple explanatory model for the absorption of substances in the form of gases or vapors was developed as far back as the I920s by Haggard (16) and Henderson & Haggard (17). It is based on the partition equilibrium between a substance in the inhaled air and the blood passing through the lungs . At equilibrium the quotient between the concentration in the blood, c B (lower-case C to indicate a variable), and the concentration in the inhaled air, C, (capital C to indicate an assumed const ant concentration), is CB/C f = S, in the following called the partition coefficient. At equilibrium C/ is equal to the concentration in the alveolar air. The size of the blood/air or water /air partition coefficient S, also known as Ostwald's coefficient, has been determined experimentally and compiled for a number of substances (I4, 28,44) (table 1). It is also assumed that the average bod ily concentration C equ als CB' The absorption into the body is govern ed according to the model presented by the following equation (32) 5 Lindqvist (28) 1. 9 Ullvarson & Ovrum (44) Trichl oroethylene 1. 3 Fiserova-Berge rova (14) 1. 7 Fis erova-Bergerova (14) 2. 5 Lindqvist (28) 1. 6 Ullvarson & Ovrum (44) o-Xylene 2.6 Fise rova-Bergero va (14) If S is much greater than 1.2, the biological halftime will be directly proportional to S according to the model. If, for instance, S = 100, then T 'h = 14 h, and the time taken to reach 90 % of the equilibrium value -according to the model -will be 45 h, equilibrium not being reached in the course of a workday. When S is on this order of magnitude, c B will increase almost linea.iy with time during a workday (the slope dc/dt of equation 1 for small values of t will be a constant , independent of S) , ie, Haber' s rule applies if it is assumed that the effect is directly proportional to c B -which is a reasonable assumption in many cases. Thus the model (equation 1) embraces Haber's rule and explains why this rule is applicable only to substances exhibiting slow elimination. Figures 1 and 2 demon strate hypothetically what happe ns according to equation 1 upon absorption into the human body under exposure to either of two different substances at the same average concentration in the air , 28 mg/rn" (= 0.028 mg/I), but in different exposure situations. One substance is assumed to have the low partition coefficient of 1 (typically substances with low water solubility and high vapor pressure). The other is assumed to have the high partition coefficient of 1 000 (typically substances with high water solubility and low vapor pressure) . In one exposure situation it is assumed that the mean concentration in the air is reached by three half-hour concentration peaks of 0.15 mg/I in air; the rest of the time the concentration is assumed to be zero (figure 1). In the other exposure situation the concentration in the air is assumed to be constant at 0.028 mg/l throughout the workday (figure 2). The final result is quite different for the two substa nces. The substance with the low partition coefficient has a blood concentration close to zero in the first case and of 0.028 mg/I (the concentration in air) in the second (figure 1). For the substance with the high partition coefficient the blood concentration in both cases is 1.1 mg/I, and the equ ilibrium value for this substance is not reached during the course of the workday (figures 1 and 2).
The assumption contained in the model is that the biotransformation of the substance in the body is of no significance, that the concentration of lipophilic substances in fatt y tissues can be disregarded, and that elimina tion by other pathways than the lungs is likewise of no significa nce. Thi s would appear to be a trouble some limitation, but the model holds fair ly well for many organic so lvents for a short time after the start of exposure, which is confirmed by comparison (reported in reference 44) with publi shed experimental human data covering exposure for 0.5 h (1,2) . On the other hand the model does not apply so well for a longer exposure period or for eliminat ion after the cessation of exposure, but this failure does not prevent it from being suita ble for a comparative discussion of what happens during continuous or intermittent exposure to substances possessing very different physical properties.
(equation 1) History of the time·weighted average and short-term exposure limits Occupational exposure limits for air contaminants are nowadays published by a large number of organizations and government agencies in various countries. In a compilation produced in 1980 by the International Labour Office the limit values from 18 countries were brought together (21). Occupational exposure limits for air contaminants have a comparatively long history, which illustrates their meaning and the philosophy behind their development.
In the beginning, the intention was to afford protection from the short-term effects of short-term exposure. In a review, Henschler (18) mentions that limit values were published for the first time by KB Lehmann in Germany. These figures concerned some organic solvents and irritative gases, such as sulfur dioxide and halogens. They were based, among other things, on the author's experiments with one employee in the laboratory. The exposure lasted for 1 h and was quantified by chemical analysis. The intention was to state the concentration that was just barely tolerable in short-time exposure. Many of Lehmann's figures, based on primitive trials of this kind, were later taken up by Henderson & Haggard (first published in 1927) (17), and the list was extended by Flury & Zernik in 1931 (15).
The most important continued development of limit values took place in the United States, particularly in connection with the ACGIH. The role of the ACGIH in the development of the TL V has recently been elucidated by a volume of reprinted key articles (26) and can also be followed in the forewords to the TLV lists issued annually by the same organization since 1946.
The maximal allowable concentration (MAC) was used for a time in the United States, eg, by the Department of Labor and Industries in Massachusetts and up to 1947 by the ACGIH (8). It was defined as the maximal allowable average concentration to which employees in industry could be exposed for 8 h daily for a long period without suffering injury or developing an occupational disease (37,43).
In 1957 the MAC concept was redefined by the American Standards Association in terms of the limit under which all variations must be held. However, this association did not publish many limit values, and therefore the definition never gained acceptance (41).
The term threshold limit value (TLV) was defined in the same way as the original term MAC by the ACGIH (26,43), meaning that during an 8-h period the concentration could be allowed to vary without restriction, as long as the average value did not exceed the set limit. Even though this definition was repeated in the forewords to the TL V lists from 1953 on, it took a long time before it became widely understood . In general, the industrial hygienists in the United States interpreted TL V as an upper limit below which all variations in the concentration of an air contaminant had to be held (43). At the same time , questions were raised as to whether it was correct to leave the variations without limits (38). Finally, the ACGIH introduced limitations on short-term concentrations in two ways, by adopting ceiling limits for some substances, applicable during a short part of the workday or shift , and by bringing in " excursion factors," by which the TWA limit values were to be multiplied in order to arrive at values for short-term variations.
Ceiling limits were used for the first time in 1963. To judge whether a ceiling limit was justified for a particular substance, the ACGIH made use of a test factor providing a link to the previously assessed TLV for the calculation of a test concentration. Substances which, at this test concentration, produced (i) intolerable irritation or (ii) chronic or irreversible tissue changes or (iii) a narcotic effect to such a degree that it affected the accident risk, ie, the ability to seek safety, or work capacity were considered to require a ceiling limit (ie, below the test concentration). For substances with a low TL V (0-1 ppm or mg/m') the test factor was put at three times the TL V. The factor then declined step by step to 1.25 times tfie TL V for substances with a high TLV (100-1 (00). During 1968-1980 it was stated in the forewords to the TL V lists that the same factors could be used as excursion factors in calculat ions of rises above the TL V-TWA, even when no ceiling limit was set.
The reasons for the factor being inversely proportional to the size of the TL V were stated in 1968 to be twofold. On the one hand, large absolute quantities ought to be avoided, and , on the other, small concentrations could not be determined with the same precision as higher ones . These ideas were further developed in 1973 by Stokinger, who stressed the rule-ofthumb character of the excursion factors. The rule was not applicable to some substances that were very irritating to the air passages , whereas it was overly strict for certain other substances, eg, carbon monoxide (42).
In 1976 it was pointed out that there is a difference in the assessment of peak concentrations depending on whether the substance in question acts rapidly or slowly. With quartz, lead, and carbon monoxide, for example, high transient concentration peaks are of no significance (unless they are very high), whereas concentration peaks for quick-acting substances such as hydrogen sulfide, ammonia, sulfur dioxide, and sensitizers had to be assessed by stricter sta ndards.
The sources do not make clear why the ACGIH nevertheless employed the formula-type assessment for limiting concentration peaks. There are a number of penetrating commentaries on this question (36,38,39). Smyth (38) pointed out in 1954 that concentration 392 peaks of some substances had an immediate effect and that TWA concentrations are not serviceable for assessing safety, since even brief excursions above the TL V of some substances can produce irritative symptoms. The same author also made the point that, for 23 010 of the substances for which the limit value was assumed to be a safeguard against narcotic effect, the TWA concentration was not applicable (39). The exposure value should not exceed a certain value irrespective of the daily average. The same arguments ought to apply to substances with an irritant effect.
Special short-term exposure limits for 142substances were published in 1964-1965 and 1967-1969 by the Department of Health in Pennsylvania (30). These limits were applicable for periods of 5, 15, or 30 min. From the published documentation (30) one can draw the conclusion that for many of these substances no safety margin for acute irritation effects or narcotic effects existed at all.
The ACGIH published short-term exposure limits for the first time in 1976. These limits constituted maximal exposure concentrations, defined as the 15-min TWA exposure that must not be exceeded at any time during a workday, even if the exposure falls short of the 8-h TWA. Exposures at the short-term limit must not last longer than 15 min, must not be repeated more than four times a day, and must be separated by intervals of at least 60 min. The shortterm exposure limit is assumed to protect the employee against the same effects as have been described with respect to the ceiling limit values. The short-term limits were based on (i) the adopted TW A-TL V levels, (ii) the aforementioned excursion factor s, (iii) the shortterm exposure limits published by the Department of Health in Pennsylvania, and (iv) limit values published by the Occupational Safety and Health Administration (OSHA) in 1971, ie, the TL V levels that were issued by the ACGIH in 1970 and published in the Federal Register (volume 36, number 105, 29 May 1971).
In 1980the ACGIH introduced a completely different, purely technically based rule for excursion s above the TLV. At present (1986-1987), there is a general limit for excursions with the aim of reducing the variability of concentrations of air contaminants to a geometric standard deviation of not more than 2.0. In order to simplify its implementation, it is recommended that the short-term exposure be allowed to exceed not more than three times the TL V for a maximum of 30 min durin g a workd ay and that under no circumstan ces may it reach five times the TL V, all under the assumpt ion that the TWA does not exceed the TL V. According to the committee there is no toxicologic foundation for short-term exposur e limits in the case of most substances.
The Federal Republi c of German y defines "Maximale Arbeit splatzkonzentrationen" -maximum workplace concentrations, abbre viated MAK -in the same way as the TLV according to the ACGIH , meaning that the German MAK committee sets limits for the TWA concentrations of substances during a normal 8-h workday. In fact there is close numerical agreement between a large number of the 1984 MAK values and the TLVs that were published in 1984-1985. However, from 1983 on the German MAK committee has used a completely different method for assessing brief peak concentrations of gaseous air contaminants (18,19). This method takes into account the way in which different substances act. Substances are classified into five categories, local irritants being assigned to category I, substances having a very weak effect with MAK values above 500 ppm to category 4, and substances with a strong odor to category 5. For these substances the short-term exposure limit is put at twice the MAK, but with variations in the permitted duration of the exposure periods and varying permissible frequency during the workday or shift. Categories 2 and 3 contain substances having systemic effects. The short-term exposure limits (STEL) for these substances are fixed with due allowance for the biological half-time of each substance. Substances with a half-time between 2 h and one workday are given short-term exposure limits corresponding to five times the MAK, while substances with half-times longer than one workday are given short-term exposure limits corresponding to ten times their MAK. The permitted excursion period is 0.5 h in these cases, while the permitted frequency varies and is smallest for substances with the longest half-time. If the height of the peak concentrations is below the permitted values, the exposure periods can be allowed to last correspondingly longer.
The background to the rules is a model for the absorption and excretion of substances based on firstorder kinetics and simplified assumptions as to the constant concentration of the air contaminant during the time the concentration peak lasts. The basic assumption is that, when a workshift is over, the exposed person will not have taken up more of the substance in his body at various concentrations in the air than he would have done if the exposure had taken place at a constant concentration corresponding to the MAK. This phenomenon is expressed by the following equations (19): where m (T STEL ) and m (T M AK ) are the absorbed quantity of the substance or metabolite after exposure to the short-term exposure limit or MAK (TWA exposure limit) concentration for the respective times, u/s is the quotient of the absorption factor a and the elimination factor E (ie, the time constant, cf, k in equation I). According to the basic assumption, m (T STEL ) must equal m (T MA K ) . The combination of equations 2 and 3 therefore describes a relationship between the TWA concentration, the peak concen-tration, and the exposure times at the respective concentrations.
The longer the duration of the exposure at the peak concentration, the lower the permissible peak concentration. Empirical values are used for the calculation, but Henschler points out that data are lacking for many substances (19).
Second to Germany, Russia is the country where occupational exposure limits for air contaminants have been in force the longest. Maximal allowable concentrations were published as early as 1922 for a number of gaseous substances, eg, hydrogen chloride and oxides of nitrogen (35). A number of Russian authors have sought to calculate limit values by using mathematical models making allowance not only for toxicologic data, but also for chemical and physical constants such as boiling point, relative molecular mass, and density (6,24,25,29). The Russian limits are keyed to a measuring period not exceeding 30 min (35,40). In the case of carbon monoxide, special rules apply to concentration peaks during periods of varying length. A number of aerosols are covered not only by maximal allowable concentrations (ie, during a measuring period of not more than 30 min), but also by limit values with respect to average values during a shift (40).
Even though the Russian limits pertain primarily to short-term exposure, they are usually lower than the corresponding TL V levels published by the ACGIH. In a comparison of limits in 1973 it was found that 88 070 of the Russian limits was lower than the corresponding values of the ACGIH (22). The explanation for this difference is that the Russian limits are based on other criteria (20,22,29), including sensitive neurophysiological test parameters and biochemical changes during examinations of experimental human subjects, as well as on results from animal experiments. Holmberg & Winell (20) found that the Russian limits are therefore lower than the corresponding American values from the ACGIH, especially in the case of organic solvents, while on the other hand the limits for irritant and lung-toxic gases and vapors, along with metals and metallic salts, are comparable in the two countries.

Concentration peaks from the toxicokinetic standpoint
The effect of concentration peaks must be discussed with due regard for the base line from which they depart, ie, the TWA concentration of the substance in question in a certain situation. In the case of highly irritating or quick-acting toxic substances, such as sulfur dioxide, acrolein, phosgene, hydrogen cyanide, and hydrogen sulfide, it is important to limit the concentration even during very short periods, and it has therefore been common practice to fix occupational exposure limits in the form of ceiling limits, with a litt le or no bear ing o n the variatio ns in th e co ncentration at the receptor level when the rat e of elimination is low. An upper limit to exposure of short duration -a matter o f hours -to dust ha s earlier been advoca ted on other gro unds, such as foul ing , effects on vision, effects on the mucous membranes of the eyes and th e upp er air pa ssages, etc .
Between these extremes, with qu ick-acting and very potent irritants and highly toxic substa nces on one side and slow-acting dusts on the other, there is a region in which the assessment of short-duration concentration peak s is complicated. Th is is true , fo r example, for most organ ic solvents and certain inorg a nic gases such as car bon monoxid e, nitric oxide (NO) and nitrous oxide (N 20 ) . TWA limits for an 8-h da y combined with rules for excursion above the se values are given for mo st of th ese substances in the TL V lists of the ACGIH and in other lists of occupational exposure limits that they have inspir ed, eg, the Swedish list and th e German MAK list.
In order to illustra te th e levels, a number of orga nic solvents have been selected from th e TL V list of the AC G IH for 1984-1985 amo ng substa nces that have o r have had techn ical importance. A tot al o f 64 substances was chosen and divided into two groups according to the critical effect or to the " chief site of action, " a term employed by the TL V committee of the ACGIH (4). T he first group comprises substa nces ha ving ma inly narcotic or irritant effects , according to th e T LV do cum en tation (4). The y are present ed in figure 3. The second group is made up of substances exerting effects on va rious organ s, according to th e same documentation (4). They are presented in table 2.
There is a po sitive correlation between TL V and vapor pressure, 0.67 (0.45-0.78 at the 95 070 level of significan ce) for the substances in figur e 3. For th e sub stances in table 2 the correlation between TL V and vapor pressure approaches significance, 0.48 (0.05-0.75 at the 95 % level of significance).
Considering the correlation between TL V and vapor pressure for the substances in figure 3, there is rea son to suppose a close agreement in relative satur ation at the limit value for the se substances. The thermodynamic activity of vapors in air is usual1y expre ssed , depending on th e cho ice of sta ndard condition , in appro ximate term s as the relati ve satur ation p /P o' where P is the current partial pressure of the substances and Po is the partial pres sur e at saturation, usual1y referred to as th e "vapor pr essure." Most tables of the vapor pressure s of substan ces express them in torrs where P TL V is th e vapor pr essure at C T LV ' the concentration at the TL V.
The thermodynamic activity (the relative saturation) at the limit value was calculated with vapor pres sure figures from reference 11 (see the legend to figure 3). Vapor pressure at 25'C sampling period that is kept as short as the measuring facilities will allow.
As for air contaminants in the form of dusts with low water solubility, elimination from the body after ingestion is slow. A deposit of the dust is built up either in the lun gs or during elimination in the particle transport system . The biological half-time of inert or fibrogenous dusts may be 500-10 000 h or more (31). Man y dusts containing heavy metals (for example, lead and cadmium), whatever their water solubility, may have a long half-time , owing to absorption in various tissues (31). It has been pointed out by man y authors (31,33,34,45) that concentration peak s in the air have  even tighter limits of 0.002 and 0.00 8. In the case of these latter substa nces, the TL V varies from 50 to 750 ppm , ie, the highest value is 15 times the lowest, while the highest acti vity is only fou r times greater than the lowest. The substa nce with the lowest relati ve saturation at the limit value is vinyl acetate . The re is reason to believe th at knowledge about its close structural relationship to carcinogenic vinyl chloride has influenced the setting of an occupational exposure limit at a lower level than what is moti vated by the medical data referred to in the docum entation. Ethylene glycol has the highest relati ve satura tion at the limit value. The high value may be due to the fact that , in sampling air contaminated by this substa nce, mist is often collected with the vapors.
For the substances with organi c effects (table 2), the varia bility of the thermodynam ic act ivity at the limit value is greater than it is for the narcotic and irritating substances ( figure 2), and, on the avera ge, their thermodynamic activities too are lower than for the latter substances. For many substances the limit values have been sharply reduced on one or more occasions. Such action has been taken, for example , for alko xy ethanols and esters, styrene and hexane, while a num-ber of chlorinated hydrocarbons with systemic effects had low activities at their limit values at quite an early stage.
From the purely technical point of view it is convenient to have a number of organi c solvents to choo se from that have occupat ional exposure limits at the same or almost the same thermodynamic activity, since both the limit value and the tendenc y to evaporate are proportional to the vapor pressure of the substances. If the manufacturer of a given product containing volatile solvents can stay below the limit value with a certa in combination of organic solvents in his plant, then he ought to be able to do the same with another combination of solvents. This assump tion can be establi shed by the follo wing simple line of argument.
Evapo ration obeys Ficks's law of diffusion. A number of more or less empirical equations has been developed to describe the rate of evaporation from sources having different geometries (for instance, according to reference 10). If all circumstances other than the nature of the evaporating substance are kept constant, the emission per unit of time will be proportional to the vapor pressure of the organic solvent. At equilibrium the air con centration, C, of the contaminant Table 2. All-time high th reshold limit value (TlV h ) set by the Amer ican Conference of Governmental Industrial Hygienists and the final year fo r this value for a number of organ ic solvents producing organ effects upon exposure at low concentrations (4). TlV for 1984/85 for the same substances and relati ve saturation at th is value (Prlv/po) calculated with vapor pressures (Po) at 25°C , taken from The Handboo k of Chemistry and Physics (11). will be proportional to the vapor pressure. At the same time the occupational exposure limit C T L V is proportional to the vapor pressure of the contaminant (ie, the occupational exposure limit is at the same relative saturation for various substances). It thus follows that c/C n . v is a constant for a number of solvents, ie, is independent of the vapor pressure and is thus independent of the substance being produced. C/C T L V is sometimes referred to as the "hygienic effect" and may pertain to one substance or to the sum of the quotients of several substances with the same mode of action in the body upon exposure. The approximate congruence among the "limit value activities" of the narcotic and irritating substances (figure 3) is probably not intentional, but is due to the reproducibility of the standard-setting procedure, ie, the fact that in a number of independent investigations the standard setters have found the same level (calculated as thermodynamic activity) for numerous substances. For instance there is nothing to suggest that the TL V committee of the ACGIH has consciously made use of the vapor pressures of the substances in order to gauge the limit values for irritant or narcotic substances. On the contrary, HE Stokinger, the committee's long-time chairman, has stated that the use of vapor pressure in calculating "MAC values" is wholly foreign to the ACGIH and is, in their view, incorrect (29).
The limit values are fixed according to medical criteria, technical and economical feasibility, and industrial experience, and therefore, analogously, similar substances (eg, homologues) are assumed to have similar effects. To the extent that medical criteria have played a part in the fixing of limit values, it may be interesting to compare the outcome with observations of thermodynamic equipotencies among a number of substances that are entirely different, first observed by Ferguson and known as Ferguson's principle (3). One explanation is that the substances act in a structurally nonspecific manner (3), in the case of narcotic substances by "fluidization" of the membranes of nerve cells, owing to the presence of lipophilic substances.
Thermodynamic equipotency has also been demonstrated in animal experiments for a number of alkylbenzenes and aliphatic alcohols whose effect is primarily irritant (12,23). The explanation given by the authors for their observation was that the substances operated through a physical mechanism affecting the trigeminal reflex. In light of their findings the authors propose that TL V levels for irritating substances be put at 3 % of the concentration that reduces the respiration of experimental animals by 50 % or 0.002-0.009 in the case of the alkylbenzenes (cf', the activities for the substances in figure 3, many of them in the range 0.002-0.008). To avoid misunderstanding, it should be mentioned that alkylbenzenes and aliphatic alcohols are assumed to exert their action in a structurally nonspecific way. Other irritants have lower ther-396 modynamic activity (relative saturation) at the level of the occupational exposure limit, for example, a number of aldehydes, such as acrolein (3 x 10-7 ) , formaldehyde (2 x 10-7 ) , and acetic aldehyde (8 x 10-5 ) . The fact that these values reflect a particularly high biological potency may indicate that the mechanism of biological action is different (3).
A comparison of the "limit-value activities" of the substances in figure 3 with published data on levels at which measurable effects appear (9,12,13,23) reveals that the safety margins for effects are often small. For the substances in figure 3, this statement applies in particular to the higher homologues of alcohols, esters, ketones, and hydrocarbons. It may be asked whether this lack of a wide safety margin is the result of the use of "analogous reasoning" in the setting of limits. If the limit for a higher homologue is put at the same volume/volume concentration as that for a lower homologue, then the thermodynamic activity of the higher homologue will be greater since the vapor pressure is lower at the higher molecular weight. In view of this fact, the correct way to apply analogous reasoning -if it is at all justified -would be to set the limits at the same thermodynamic activity of the substances in question.
Another aspect to be considered is that, if a substance has effects other than narcotic ones, including biotransformation, then not only the activity, but also the concentration expressed as moles per kilogram is of interest from the toxicologic standpoint, since the inactivation system of the body is burdened in proportion to the mole concentration. At equilibrium, substances with a high blood/air partition coefficient will have been absorbed to a higher concentration than substances with a low blood/air partition coefficient when the thermodynamic activities are the same. The following reasoning illustrates this point. Substance I is assumed to have a vapor pressure of I torr and a partition coefficient of I. Substance 2 is assumed to have a vapor pressure of 100 torrs and a partition coefficient of I 000. It is assumed that the occupational exposure limit of both substances, expressed as thermodynamic activity, is 0.005. After an 8-h exposure to a steady concentration at the limit value, the blood concentration of the two substances according to equation I will be as follows: substance I = 20 ug/I, substance 2 = 80 000 ug/l. In practice, no substance would satisfy the simple equations for so long a time as 8 h because of biotransformation and excretion through paths other than pulmonary ventilation, but the difference in the quantity of substance that passes through the body and burdens the inactivition systems can for this reason be still greater than is implied by the calculation.

Conclusions
Occupational exposure limits for gases and vapors have been developed in different countries in a stereotyped manner th at mak es little allowance for the individual properties of th e substances. This developm ent is particularly true with regard to short-term exposure limits. There are not sufficient toxicologic data to warrant occupation al short-term exposur e limits for the majority of substances. In this article the literatu re on expo sure to concentration peaks is reviewed , and the problem is ana lyzed from general toxico kinetic and phy sicochemical points of view.
It would probably not be economically and practically po ssible to put together su fficient exposure data to permit epidemiologic anal ysis concerni ng the effect of short-term exposure for the majority of substances. The greater part of the available expo sur e data has been co llected with the aim of checking on adherence to the rules in force. The mea surements are therefore performed in a stereotyped manner . These rules, which have been formulated from inadequ ate knowledge, ha ve in thi s way militated against the glean ing of new knowledge.
On e way to deal with the situation for many fast or moderately fast acting gaseous subst ances would be to apply th e available toxicokinetic knowledge as described for instance by the German MAK committ ee (18,19). As this is a rather complicated pro cedure and the data needed are lacking for many substances, a much simpler route is to define the occupational expo sur e limits for th is kind of su bstances as ceiling limit s. In order to illustrate the consequences of such a step , data from a large number of workplace measurements co llated by Leidel and his co-workers (27) can be used. The concentration readings exhibit a logarithmic normal distribution. The geometric sta ndard deviati on varies a great deal and shows no regularit y. Geometric standard deviations in the range from 1.5 to 2 are common, however. If concentration values in a given situation have a geometric standar d deviat ion o f 2.0, it means that 5 % of all values exceed 3.13 (ie, el. 64S1n2 ) times the geometric mean. This figure indicates that the concentration must go substantially below a limit value in many ordinary cases if the probability that the limit will be exceeded is not to become unacceptably great. The matter has been discussed further by Leidel et al (27).
Th e review and the analysis sugge st several ways to ach ieve better standards for the assessment of concentration peaks. One straightforward and reasonably simple way to deal with the matter is summarized in the following thr ee points, which should be considered in the sett ing of occupational exposure limits.
I. For substa nces producing th eir act ion fast or moderately fast -in less than an hour -ceiling limits only should be con sidered. Therefore, not only a number of highly irritating or quick-acting toxic substances such as sulfur dio xide, acrolein, phosgene, hydrogen cyanide, and hydrogen sulfide sho uld be given ceiling limits, but also a number of organic solvents with low water/ air partition coefficients (typically lower aliphat-ic and aromatic hydrocarbons and halo genated hydrocarbons with narcosis or irritation as the critical effect) which now ha ve TWA exposure limits.
2. When structure analogy is justified in the setting of occupational exposure limits for narcotic and irritating gases, the correct way is to set the limits at the same thermodynamic activit y (relative saturation) of the su bstances in que stion and not at the same concentration .
3. For subst ances which are absorbed and eliminated slowly -a matter of hours or more -timeweighted exposure limits are appropriate, but the possible accumulation of large absolute quantities of the substances should be considered. Th is point is particularly important when the critical effect is structurally nonspecific narcosis or irritation, as the thermodynamic equipotency of these substances means that the effective concentration in persons exposed to watersoluble gases and vapors is higher than the corresponding concentration of substances with low water solubility.