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Toxicologic considerations in the diagnosis of occupational asthma
Toxicologic considerations in the diagnosis of occupational asthma William J Waddell, MD*
Background: The consideration of dose for chemicals inducing occupational asthma is examined from the point of view of a toxicologist. Two widely used chemicals in industry, toluene diisocyanate (TDI) and formaldehyde, are used as examples of agents that are formally recognized by OSHA to cause occupational asthma. The Permissible Exposure Limit (PEL) of OSHA and the Threshold Limit Value (TLV) of ACGIH for TDI are identical and are in the range of values for which occupational asthma has been reported in some workers. The narrow range of exposure values for TDI in studies of workers with and without asthma is discussed and correlated with the background concentration of TDI in the ambient atmosphere. For formaldehyde, the PEL and TLV, in contrast, offer a wide margin of safety for the inducement of occupational asthma. Conclusion: From this disparity in exposure limits for TDI and formaldehyde, it is concluded that occupational exposure limits by agencies for specific chemicals do not provide a reliable indication of the concentration of a chemical that is necessary to produce occupational asthma. The need for a better appreciation of dose response, particularly relative to background, ambient levels, in the evaluation of occupational asthma is emphasized. Ann Allergy Asthma Immunol 1999;83:618– 623.
INTRODUCTION At the outset, it is useful to remember the statement of Paracelsus, “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.” This observation today is firmly established from the recognition that chemical reactions in biologic systems follow the law of mass action from the chemical potential of substances in that system. Although this is well recognized and accepted in classical toxicology, apparently there are many who do not fully appreciate how this dictum also applies to allergic mechanisms. One purpose of this review is to help emphasize the significance of dose in allergic reactions and in occupational asthma. The dosage range, of course, may be much lower in allergic sensi* Professor and Chairman, Emeritus, Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, Kentucky. Received for publication May 1, 1999. Accepted for publication in revised form August 24, 1999.
618
tivity reactions to a chemical than it is in direct toxic effects; nevertheless, there is a dose in sensitivity reactions causing occupational asthma below which there is no response as well as a dose-response curve for sensitivity. Two important aspects of this application of Paracelsus’ principle to occupational asthma is that a threshold dose is necessary to both sensitize and induce occupational asthma. Second, the converse is true, ie, exposure can exist throughout life to chemicals at doses below the threshold for sensitization or induction of asthma. HOW TO DIAGNOSE OCCUPATIONAL ASTHMA There are several recent reviews on the diagnosis and management of occupational asthma1– 4 that may be summarized into four diagnostic steps for the determination of occupational asthma. It is not the purpose of this paper to expand on these reviews. To summarize briefly: first, of course, is a history: the occupational history and timing of the onset of symptoms with
potential exposure; ascertainment of whether co-workers have had similar signs and symptoms; information about possible effects on other organs; and information about allergic sensitivity to other chemicals that might indicate that the patient is an atopic individual. The second step is an exposure assessment. Industrial hygiene measurements should be available and these can be compared with the American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Values (TLVs) and the Occupational Safety and Health Administration (OSHA) Permissible Exposure Limits (PELs). The National Institute for Occupational Safety and Health (NIOSH) Recommended Exposure Limits (RELs) are only recommended values and should not be accepted as indicating an adverse effect since they may be overly conservative. Some of these values may be found in Material Safety Data Sheets (MSDS) but MSDSs should not be considered sources of authoritative toxicologic information. These Sheets are prepared primarily to satisfy legal requirements and the limited toxicologic information on the MSDSs can readily be taken out of context and misinterpreted. Sources of more reliable, detailed toxicity information on specific chemicals include the free Website HSDB online database,5 MEDLINE,6 toxicology texts, eg, Sullivan & Krieger,7 Ellenhorn,8 Casarett and Doull,9 Hayes,10 ACGIH TLV Documentations11 and Toxicological Profiles available from The Agency for Toxic Substances and Disease Registry (ATSDR).12 Physiologic evaluations would be the third step; pulmonary function tests (PFT) which include peak expiratory flow rate (PEFR) should be done;
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
methacholine challenge is useful for a determination of the presence of bronchial hyperreactivity. Challenge testing with specific chemicals suspected of being pulmonary allergens should only be done in a setting prepared to deal with the potential dangers involved. The final step would be immunologic evaluations. Although these could include IgE and IgG antibody levels, skin tests and radioallergosorbent tests (RAST), consideration for the appropriateness of such tests depends on the specific chemical.1,3,4 Establishing causation for occupational asthma from a specific chemical may be more difficult than imagined. It is quite problematic if the concentration of the chemical is low and especially if the exposure levels are below the OSHA PEL and ACGIH TLV values. There may be also the possibility of synergism between mixtures of chemicals. Collaboration with a toxicologist may be helpful, but do not overlook the possible contribution of temperature, humidity, lighting, vibration, noise, and other physical factors. Also, of great importance in today’s climate of chemophobia and litigation is the possible overlay of anxiety and other non-physical factors such as monetary gain from causation by an occupational chemical. GOVERNMENTAL AGENCIES OVERSEEING OCCUPATIONAL DISEASE There are two agencies in the United States that promulgate standards for occupational exposure to chemicals. The ACGIH has been setting guideline standards for over 50 years while OSHA was established in 1970 and provides legally binding exposure limits. Although many values are the same for these two agencies, there are some differences which are to be expected when two independent groups of scientists examine the same relevant literature. The OSHA list of agents13 associated with the development of occupational asthma provides a baseline reference source, although this agency makes no distinction between sensitiz-
VOLUME 83, DECEMBER, 1999
ing and non-sensitizing agents. Any agent in the occupational environment that has been reported in the literature to be “associated” with asthma is recognized by OSHA as a possible asthma-inducing agent. Occupational Safety and Health Administration makes no specific adjustments in the PELs for such agents, but there is informal recognition of more than 200 agents that have been “associated” with occupational asthma. These may be summarized as: high molecular weight plant and animal dusts and plant and animal proteins such as those associated with grain dust, laboratory animals and proteins in natural rubber latex; low molecular weight reactive chemicals such as diisocyanates and platinum salts; pharmaceuticals that cause sensitizing asthma such as penicillin, psyllium, and cephalosporins; and non-sensitizing respiratory irritants such as chlorine gas, sulfur dioxide, and fire smoke. Further, specific information can be found on the OSHA Website.13 Formal recognition is given to only three substances: isocyanates, latex, and formaldehyde. This review will consider some of the details of isocyanate asthma and formaldehyde asthma as examples to illustrate the disparity in exposure limits and the significance and importance of dose; a lack of appreciation of the importance of dose has confused some of the literature on these two chemicals and many others. DIISOCYANATES The ACGIH “Sensitizer” notation, which first appeared in 1997, is defined as the confirmed potential for worker sensitization as a result of dermal contact and/or inhalation exposure based on the weight of scientific evidence. Lack of the sensitizer notation does not necessarily mean that the substance is not a sensitizer. As of the TLV booklet published in 1998,14 the ACGIH proposed (Notice of Intended Changes) only six substances as sensitizers: N-butyl acrylate, gluteraldehyde, 2-hydroxypropyl acrylate, methyl vinyl ketone, toluene-
2,4- or toluene-2,6-diisocyanate (TDI), and wood dust (all types). Toluene Diisocyanate The ACGIH TLV and OSHA PEL for TDI are both 0.005 ppm (0.036 mg/ m3). Although this may appear to be a low concentration, it is important to point out that this is 1.2 ⫻ 1017 molecules/m3 of air. There is probably no such thing as a zero concentration of TDI in any ambient atmosphere. The estimated half-life of TDI in the atmosphere is two days, and there was a release of 141 kilograms per day into the air in the United States in 1990 from industrial sources15; this is similar to releases from 1990 through 1996. Even if this amount was uniformly diluted in the total volume of air on earth (4 ⫻ 1018 cubic meters), the equilibrium concentration of TDI in the atmosphere calculable from this information would be 5.6 ⫻ 108 molecules/m3; this is clearly a conservative estimate since there is considerable release from sources outside the United States. Obviously, there is a background concentration present at all times and the question is the threshold concentration necessary to precipitate an asthmatic response. There are several possible mechanisms for the production of occupational asthma by isocyanates. These include pharmacologic; irritative; direct toxic effects from exposure to high levels; or immunologic.16 The pharmacologic mechanisms that have been proposed in the literature include -adrenergic blockade,17 and inhibition of acetylcholinesterase and prostaglandin receptors.18 The pharmacologic mechanisms are probably the least clearly established, and in concentrations sufficient to cause direct toxicity are rarely, if ever, encountered in occupational environments. An example of direct toxic effects from high exposures was seen in the Bhopal disaster. Immunologic mechanisms may include IgE, IgG, or release of cytokines such as histamine-releasing factors and tumor necrosis factor alpha from peripheral mononuclear cells.19 –22 Although some immunologic mecha-
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nisms have been demonstrated, these mechanisms have not been seen consistently in patients with isocyanate asthma. Table 1 shows the results of a study by Kim et al23 on specific IgE and IgG levels in isocyanate workers diagnosed with asthma by PEFR. Neither IgE nor IgG was diagnostic. Others1,2,4 have also come to the same conclusion. The TLV for TDI is the ACGIH Chemical Substances Committee’s consensus for a protective value based on the Committee’s judgment of reports in the literature. The concentration for individuals reported to be sensitive to TDI is remarkably close to the concentration for individuals not sensitive. There were a total of 19 reports over the time interval of 1947 to 1983 in the 1998 ACGIH Documentation. In those reports on individuals that were sensitized, the median level was 0.02 ppm of TDI and for those not sensitized the level was 0.01 ppm (Table 2); however, the range in the reports actually overlapped. It is remarkable how steep the dose-response or sharp the threshold is thought to be; there is no apparent margin of safety in this TLV value. The dose response for sensitization to TDI is further illustrated in Table 3 using the data of Wegman et al.24 The level of no response is less than onehalf of the highest value that was used for an adverse effect level; the response shows an effect at 0.0035 ppm which is below the ACGIH TLV and OSHA PEL. One may question whether the TLV and PEL are sufficiently protective. Figure 1 is a graph
Table 2. Studies from which ACGIH Set the TLV for TDI Based on Decrement in PFT* ppm of TDI Sensitized
Not Sensitized
0.003 0.9 0.02†
0.001 0.03 0.01‡
Lowest level Highest level Median level
* Data from a total of 19 reports from the time interval of 1947–1983; mostly grab samples (11). † 7 of 14 reports. ‡ 1 of 5 reports. Table 3. Dose Response for Sensitization to TDI of Workers at Ambient Air Exposures* ppm of TDI in Ambient Air
mL/yr Decline in FEV1
⬍0.002 0.002–0.003 ⬎0.0035
0 42 204
* Data from Wegman et al.24
of these doses on a scale of molecules/m3 of air. This scale was introduced by Rozman et al25 in an analysis of cancer risk assessment but it is excellent to illustrate relative doses to the lungs responsible for occupational asthma. This molecular scale starts on the abscissa with one molecule/m3 (the lowest possible dose). There appears to
be a psychologic barrier, even among physicians and scientists, to the realization that concentrations in ppm and ppb are over a very narrow range and that an enormous number of molecules are still present even at ppb and ppt. This figure shows the steep dose response of the Wegman data in relation to the TLV and PEL (12 ⫻ 1016 molecules/m3 for TDI). Also shown is the minimum concentration (5.6 ⫻ 108 molecules/m3) in the air worldwide calculated above from release from sources in the United States and the decomposition rate of TDI in the atmosphere. The points to be emphasized from Figure 1 are (A) that the dose response is steep for decrements in pulmonary function from TDI, (B) the TLV and PEL for TDI apparently are too high for protection of all workers, and (C) there is obviously a threshold somewhere in the vicinity of 1015 to 1016 molecules/m3 below which asthma may never be seen. HEXAMETHYLENE DIISOCYANATE Table 4 shows the range of doses for the lowest observed adverse effect level (LOAEL) and the no observed adverse effect level (NOAEL) for hexamethylene diisocyanate (HDI) from a survey of the literature by ATSDR26 together with the number of
Table 1. Specific IgE and IgG Levels in Isocyanate Workers Diagnosed with Asthma by PEFR* Asthma by PEFR
Increased IgE Not Increased Increased IgG Not Increased * Data from Kim et al.23
620
Yes
No
3 5 1 7
6 67 8 65
Figure 1. Molecules of TDI per cubic meter of air plotted on the logarithmic molecular scale of Rozman et al25 against the mL per year decline in FEV1 of workers exposed to three levels of TDI in the workplace (data of Wegman et al24). Also indicated on the abscissa is the TLV and PEL (0.005 ppm; 1.2 ⫻ 1017 molecules/m3) and the minimum worldwide concentration in air of TDI (5.6 ⫻ 108 molecules/m3); see text for calculation.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Table 4. Range of Doses for Adverse Respiratory Effects in Humans for Hexamethylene Diisocyanate* ● Lowest observed adverse effect level: 0.006 ppm to 0.0001 ppm (1.5 ⫻ 100,000,000,000,000,000 molecules/m3 to 2.4 ⫻ 1,000,000,000,000,000 molecules/m3) ● No observed adverse effect level: 0.0006 ppm (1.5 ⫻ 10,000,000,000,000,000 molecules/m3) * Calculated from data of ATSDR Toxicological Profile.26
molecules/m3 in air for each of these concentrations. When expressed as numbers of molecules, the steep doseresponse curve and the overlap between the LOAEL and NOAEL are apparent. Figure 2 shows these data plotted on the logarithmic molecular scale of Rozman et al.25 This visualization further emphasizes the narrow range over which concentrations are assessed for regulatory and causation purposes. FORMALDEHYDE The ACGIH Ceiling for formaldehyde is 0.3 ppm (0.37 mg/m3) and the OSHA PEL is 0.75 ppm (0.92 mg/m3). Note that 0.37 mg/m3 is 7.4 ⫻ 1018 molecules/m3. It is clearly impossible to avoid formaldehyde. Indeed, formaldehyde is an essential compound in intermediary metabolism of all animals and plants. The concentration in the blood of normal, healthy humans is 2.6 ppm.27 It can be calculated that 58 g are produced daily in intermediary metabolism in adult humans.7 The concentration in mainstream cigarette smoke ranges from 47 to 214 ppm.28 There are, however, at least five studies29 –33 that show no adverse effect of formaldehyde on asthmatics at concentrations of about 3 ppm. The original report by Hendrick and Lane34 on formaldehyde-induced asthma in nurses working in a renal dialysis unit was the consequence of heavy exposure to formaldehyde for many years. This report generated unwarranted, speculative extrapolation of asthma in individuals exposed to much lower concentrations. There are no reliable reports of asthma being produced in individuals at levels anywhere near the TLV or PEL; those values were set by
VOLUME 83, DECEMBER, 1999
these agencies at the very minimal irritation levels for conjunctiva and nasal epithelium and partially in response to the formaldehyde fears of the 1980s. One should certainly not confuse the TLV and PEL for formaldehyde as levels at or even above which one might induce asthma. The TLV and PEL for formaldehyde are in contrast to the TLV and PEL for TDI and HDI. There is an overlap of these regulatory values for the diisocyanates with concentrations reported in the literature that have adverse effects on pulmonary function. For formaldehyde, there is a generous margin of safety for this ubiquitous and essential compound. The message to be made is that TLVs and PELs may or may not offer a margin of safety. The practicing physician cannot accept these values with the degree of trust one would like. Unfortunately, further information may be needed for a conclusion of causality.
ADDITIVE EFFECTS The question always arises about additive effects from mixtures of chemicals. The ACGIH (Table 5) provides a formula for calculating additive effects when the substances act on the same organ system, presumably by the same mechanism. Also included in the Table is the formula for calculating the permissible TLV concentration when the effects are independent, ie, act on different organs by presumably different mechanisms. Again the decision on the effect of mixtures can be difficult and may require consultation with one quite knowledgeable about the chemicals involved. In conclusion, occupational asthma has been associated with many agents of diverse structures. Some of these associations may be due to allergic mechanisms but for many of them the allergic mechanism has not been demonstrated. For the isocyanates, which are probably the most common cause of occupational asthma, an allergic mechanism has not been conclusively demonstrated for inducing asthma. The TLV and PEL for isocyanates may not be protective for all workers. The concentrations observed to have an effect, or no effect, are all in a very narrow range. For formaldehyde, the original report of asthma in nurses working in a renal dialysis unit engendered an extrapolation to doses lower than neces-
Figure 2. Molecules of HDI per cubic meter of air plotted on the logarithmic molecular scale of Rozman et al.25 Indicated on the abscissa are the range of values for the LOAEL and the NOAEL reported in the ATSDR Toxicological Profile26 for HDI.
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Table 5. ACGIH Position on Mixtures* ● Additive effects (“substances which act upon the same organ system”) C1/TLV1 ⫹ C2/TLV2 ⫹ C3/TLV3 ⫹ . . . ⫽ 1 ● Independent effects (“purely local effects on different organs of the body”) C1/TLV1 ⫽ 1; C2/TLV2 ⫽ 1; C3/TLV3 ⫽ 1; etc.
20.
* Formulas from ACGIH.14
21.
sary to prevent occupational asthma. Current limits in industry on formaldehyde provide a wide safety margin for formaldehyde in the production of occupational asthma. Finally, it should be recognized that a zero concentration for any substance in air is probably unobtainable and indeed even unnecessary. Fortunately, however, it is probably not necessary to have a concentration of zero for any chemical because dose-response information suggests there is a threshold of many molecules per liter of inhaled air at which there is no response. ACKNOWLEDGMENT The author expresses his grateful appreciation to Dr. Laszlo Kerecsen for preparation of the figures expressing dosage on a molecular scale. REFERENCES 1. Bernstein DI. Allergic reactions to workplace allergens. JAMA 1997;278: 1907–1913. 2. Chan-Yeung M. Occupational asthma. Chest 1990;98(Suppl):148S–161S. 3. Chan-Yeung M. Occupational asthma. Environ Health Perspect 1995; 103(Suppl 6):249 –252. 4. Newman LS. Occupational asthma— diagnosis, management, and prevention. Clin Chest Med 1995;16: 621– 636. 5. HSDB (Hazardous Substances Data Bank) [TOXNET database online]. http: //toxnet.nlm.nih.gov/servlets.simplesearch?1.5.1.367. Bethesda, Maryland: National Library of Medicine. 6. MEDLINE (database online). Bethesda, Maryland: National Library of Medicine. 7. Sullivan JB, Krieger GR, eds. Hazardous materials toxicology. Clinical principles of environmental health. Baltimore: Williams & Wilkins, 1992. 8. Ellenhorn MJ. Ellenhorn’s medical toxicology: diagnosis and treatment of
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9.
10. 11.
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human poisoning. Second Edition. Baltimore: Williams & Wilkins, 1997. Klaassen CD, ed. Casarett and Doull’s toxicology: the basic science of poisons. Fifth Edition. New York: McGraw-Hill, 1996. Hayes AW, ed. Principles and methods of toxicology. Third Edition. New York: Raven Press, 1994. American Conference of Governmental Industrial Hygienists. 1998 TLVs® and BEIs®: Documentations for Threshold Limit Values for chemical substances and physical agents. Cincinnati: ACGIH, 1998. Agency for Toxic Substances and Disease Registry. Toxicological Profiles. Atlanta, Georgia: US Department of Health and Human Services. Occupational Safety and Health Administration (OSHA) Database on Occupational Asthma. (http:// www.osha.gov/oshinfo/priorities. asthma.html.) American Conference of Governmental Industrial Hygienists. 1998 TLVs® and BEIs®: Threshold Limit Values for chemical substances and physical agents. Biological Exposure Indices. Cincinnati: ACGIH, 1998. Toxic Release Inventory (TRI90) [TOXNET database online]. http:// toxnet.nlm.nih.gov/servlets/simplesearch?1.15.1.367. Bethesda, Maryland: National Library of Medicine. Deschamps F, Prevost A, Lavaud F, Kochman S. Mechanisms of occupational asthma induced by isocyanates. Ann Occup Hyg 1998;42:33–36. Butcher B, Karr RM, O’Neil CE, et al. Inhalation challenge and pharmacologic studies of toluene diisocyanate (TDI)-sensitive workers. J Allergy Clin Immunol 1979;64:146 –152. Wass U, Belin L. Immunologic specificity of isocyanate-induced IgE antibodies in serum from sensitized workers. J Allergy Clin Immunol 1989;83: 126 –135. Herd Z, Bernstein DI. Antigen specific histamine releasing factors in diisocya-
22.
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27.
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30.
nate induced occupational asthma. Am J Respir Crit Care Med 1994;150: 988 –994. Lummus ZL, Alam R, Bernstein JA, Bernstein DI. Characterization of histamine releasing factors in diisocyanate-induced occupational asthma. Toxicology 1996;111:191–206. Maestrelli D, di Stafano A, Occari P, et al. Cytokines in the airway mucosa of subjects with asthma induced by toluene diisocyanate. Am J Respir Crit Care Med 1995;151:607– 612. Siracusa A, Vecciarelli A, Brugnami G, et al. Changes in interleukin-1 and tumor necrosis factor production by peripheral blood monocytes after specific bronchoprovocation test in occupational asthma. Am Rev Respir Dis 1992;146:408 – 412. Kim H, Kim Y-D, Choi J. Seroimmunological characteristics of Korean workers exposed to toluene diisocyanate. Environ Res 1997;75:1– 6. Wegman DH, Musk AW, Main DM, Pagnotto LD. Accelerated loss of FEV 1 in polyurethane production workers: a four-year prospective study. Am J Ind Med 1982;3:209 –215. Rozman KK, Kerecsen L, Viluksela MK, et al. A toxicologist’s view of cancer risk assessment. Drug Metab Rev 1996;28:29 –52. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for hexamethylene diisocyanate. Atlanta: US Department of Health and Human Services, Public Health Service, 1998. Heck Hd’A, Casanova-Schmitz M, Dodd PB, et al. Formaldehyde (CH2O) concentrations in the blood of humans and Fischer-344 rats exposed to CH2O under controlled conditions. Am Ind Hyg Assoc J 1985;46:1–3. Gori G, Lynch CJ, Nightingale TE, et al. Constituents of tobacco smoke. In: Pinney JM, ed. Smoking and health: a report of the Surgeon General. Washington, DC: US Department of Health, Education, and Welfare, Publication No. 79-50066. 1979:14 – 43. Frigas E, Filley WV, Reed CE. Bronchial challenge with formaldehyde gas: lack of bronchoconstriction in 13 patients suspected of having formaldehyde-induced asthma. Mayo Clin Proc 1984;59:295–299. Sheppard D, Eschenbacher WL, Epstein J. Lack of bronchomotor response to up to 3 ppm formaldehyde in
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
subjects with asthma. Environ Res 1984;35:133–139. 31. Green DJ, Sauder LR, Kulle TJ, Bascom R. Acute response to 3.0 ppm formaldehyde in exercising healthy nonsmokers and asthmatics. Am Rev Respir Dis 1987;135:1261–1266.
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32. Uba G, Pachorek D, Bernstein J, et al. Prospective study of respiratory effects of formaldehyde among healthy and asthmatic medical students. Am J Ind Med 1989;15:91–101. 33. Witek TJ Jr, Schachter EN, Tosun T, et al. An evaluation of respiratory effects
following exposure to 2.0 ppm formaldehyde in asthmatics: lung function, symptoms, and airway reactivity. Arch Environ Health 1987;42:230 –237. 34. Hendrick DJ, Lane DJ. Formalin asthma in hospital staff. Brit Med J 1975;1:607– 608.
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Background: The consideration of dose for chemicals inducing occupational asthma is examined from the point of view of a toxicologist. Two widely used chemicals in industry, toluene diisocyanate (TDI) and formaldehyde, are used as examples of agents that are formally recognized by OSHA to cause occupational asthma. The Permissible Exposure Limit (PEL) of OSHA and the Threshold Limit Value (TLV) of ACGIH for TDI are identical and are in the range of values for which occupational asthma has been reported in some workers. The narrow range of exposure values for TDI in studies of workers with and without asthma is discussed and correlated with the background concentration of TDI in the ambient atmosphere. For formaldehyde, the PEL and TLV, in contrast, offer a wide margin of safety for the inducement of occupational asthma. Conclusion: From this disparity in exposure limits for TDI and formaldehyde, it is concluded that occupational exposure limits by agencies for specific chemicals do not provide a reliable indication of the concentration of a chemical that is necessary to produce occupational asthma. The need for a better appreciation of dose response, particularly relative to background, ambient levels, in the evaluation of occupational asthma is emphasized. Ann Allergy Asthma Immunol 1999;83:618– 623.
INTRODUCTION At the outset, it is useful to remember the statement of Paracelsus, “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.” This observation today is firmly established from the recognition that chemical reactions in biologic systems follow the law of mass action from the chemical potential of substances in that system. Although this is well recognized and accepted in classical toxicology, apparently there are many who do not fully appreciate how this dictum also applies to allergic mechanisms. One purpose of this review is to help emphasize the significance of dose in allergic reactions and in occupational asthma. The dosage range, of course, may be much lower in allergic sensi* Professor and Chairman, Emeritus, Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, Kentucky. Received for publication May 1, 1999. Accepted for publication in revised form August 24, 1999.
618
tivity reactions to a chemical than it is in direct toxic effects; nevertheless, there is a dose in sensitivity reactions causing occupational asthma below which there is no response as well as a dose-response curve for sensitivity. Two important aspects of this application of Paracelsus’ principle to occupational asthma is that a threshold dose is necessary to both sensitize and induce occupational asthma. Second, the converse is true, ie, exposure can exist throughout life to chemicals at doses below the threshold for sensitization or induction of asthma. HOW TO DIAGNOSE OCCUPATIONAL ASTHMA There are several recent reviews on the diagnosis and management of occupational asthma1– 4 that may be summarized into four diagnostic steps for the determination of occupational asthma. It is not the purpose of this paper to expand on these reviews. To summarize briefly: first, of course, is a history: the occupational history and timing of the onset of symptoms with
potential exposure; ascertainment of whether co-workers have had similar signs and symptoms; information about possible effects on other organs; and information about allergic sensitivity to other chemicals that might indicate that the patient is an atopic individual. The second step is an exposure assessment. Industrial hygiene measurements should be available and these can be compared with the American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Values (TLVs) and the Occupational Safety and Health Administration (OSHA) Permissible Exposure Limits (PELs). The National Institute for Occupational Safety and Health (NIOSH) Recommended Exposure Limits (RELs) are only recommended values and should not be accepted as indicating an adverse effect since they may be overly conservative. Some of these values may be found in Material Safety Data Sheets (MSDS) but MSDSs should not be considered sources of authoritative toxicologic information. These Sheets are prepared primarily to satisfy legal requirements and the limited toxicologic information on the MSDSs can readily be taken out of context and misinterpreted. Sources of more reliable, detailed toxicity information on specific chemicals include the free Website HSDB online database,5 MEDLINE,6 toxicology texts, eg, Sullivan & Krieger,7 Ellenhorn,8 Casarett and Doull,9 Hayes,10 ACGIH TLV Documentations11 and Toxicological Profiles available from The Agency for Toxic Substances and Disease Registry (ATSDR).12 Physiologic evaluations would be the third step; pulmonary function tests (PFT) which include peak expiratory flow rate (PEFR) should be done;
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
methacholine challenge is useful for a determination of the presence of bronchial hyperreactivity. Challenge testing with specific chemicals suspected of being pulmonary allergens should only be done in a setting prepared to deal with the potential dangers involved. The final step would be immunologic evaluations. Although these could include IgE and IgG antibody levels, skin tests and radioallergosorbent tests (RAST), consideration for the appropriateness of such tests depends on the specific chemical.1,3,4 Establishing causation for occupational asthma from a specific chemical may be more difficult than imagined. It is quite problematic if the concentration of the chemical is low and especially if the exposure levels are below the OSHA PEL and ACGIH TLV values. There may be also the possibility of synergism between mixtures of chemicals. Collaboration with a toxicologist may be helpful, but do not overlook the possible contribution of temperature, humidity, lighting, vibration, noise, and other physical factors. Also, of great importance in today’s climate of chemophobia and litigation is the possible overlay of anxiety and other non-physical factors such as monetary gain from causation by an occupational chemical. GOVERNMENTAL AGENCIES OVERSEEING OCCUPATIONAL DISEASE There are two agencies in the United States that promulgate standards for occupational exposure to chemicals. The ACGIH has been setting guideline standards for over 50 years while OSHA was established in 1970 and provides legally binding exposure limits. Although many values are the same for these two agencies, there are some differences which are to be expected when two independent groups of scientists examine the same relevant literature. The OSHA list of agents13 associated with the development of occupational asthma provides a baseline reference source, although this agency makes no distinction between sensitiz-
VOLUME 83, DECEMBER, 1999
ing and non-sensitizing agents. Any agent in the occupational environment that has been reported in the literature to be “associated” with asthma is recognized by OSHA as a possible asthma-inducing agent. Occupational Safety and Health Administration makes no specific adjustments in the PELs for such agents, but there is informal recognition of more than 200 agents that have been “associated” with occupational asthma. These may be summarized as: high molecular weight plant and animal dusts and plant and animal proteins such as those associated with grain dust, laboratory animals and proteins in natural rubber latex; low molecular weight reactive chemicals such as diisocyanates and platinum salts; pharmaceuticals that cause sensitizing asthma such as penicillin, psyllium, and cephalosporins; and non-sensitizing respiratory irritants such as chlorine gas, sulfur dioxide, and fire smoke. Further, specific information can be found on the OSHA Website.13 Formal recognition is given to only three substances: isocyanates, latex, and formaldehyde. This review will consider some of the details of isocyanate asthma and formaldehyde asthma as examples to illustrate the disparity in exposure limits and the significance and importance of dose; a lack of appreciation of the importance of dose has confused some of the literature on these two chemicals and many others. DIISOCYANATES The ACGIH “Sensitizer” notation, which first appeared in 1997, is defined as the confirmed potential for worker sensitization as a result of dermal contact and/or inhalation exposure based on the weight of scientific evidence. Lack of the sensitizer notation does not necessarily mean that the substance is not a sensitizer. As of the TLV booklet published in 1998,14 the ACGIH proposed (Notice of Intended Changes) only six substances as sensitizers: N-butyl acrylate, gluteraldehyde, 2-hydroxypropyl acrylate, methyl vinyl ketone, toluene-
2,4- or toluene-2,6-diisocyanate (TDI), and wood dust (all types). Toluene Diisocyanate The ACGIH TLV and OSHA PEL for TDI are both 0.005 ppm (0.036 mg/ m3). Although this may appear to be a low concentration, it is important to point out that this is 1.2 ⫻ 1017 molecules/m3 of air. There is probably no such thing as a zero concentration of TDI in any ambient atmosphere. The estimated half-life of TDI in the atmosphere is two days, and there was a release of 141 kilograms per day into the air in the United States in 1990 from industrial sources15; this is similar to releases from 1990 through 1996. Even if this amount was uniformly diluted in the total volume of air on earth (4 ⫻ 1018 cubic meters), the equilibrium concentration of TDI in the atmosphere calculable from this information would be 5.6 ⫻ 108 molecules/m3; this is clearly a conservative estimate since there is considerable release from sources outside the United States. Obviously, there is a background concentration present at all times and the question is the threshold concentration necessary to precipitate an asthmatic response. There are several possible mechanisms for the production of occupational asthma by isocyanates. These include pharmacologic; irritative; direct toxic effects from exposure to high levels; or immunologic.16 The pharmacologic mechanisms that have been proposed in the literature include -adrenergic blockade,17 and inhibition of acetylcholinesterase and prostaglandin receptors.18 The pharmacologic mechanisms are probably the least clearly established, and in concentrations sufficient to cause direct toxicity are rarely, if ever, encountered in occupational environments. An example of direct toxic effects from high exposures was seen in the Bhopal disaster. Immunologic mechanisms may include IgE, IgG, or release of cytokines such as histamine-releasing factors and tumor necrosis factor alpha from peripheral mononuclear cells.19 –22 Although some immunologic mecha-
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nisms have been demonstrated, these mechanisms have not been seen consistently in patients with isocyanate asthma. Table 1 shows the results of a study by Kim et al23 on specific IgE and IgG levels in isocyanate workers diagnosed with asthma by PEFR. Neither IgE nor IgG was diagnostic. Others1,2,4 have also come to the same conclusion. The TLV for TDI is the ACGIH Chemical Substances Committee’s consensus for a protective value based on the Committee’s judgment of reports in the literature. The concentration for individuals reported to be sensitive to TDI is remarkably close to the concentration for individuals not sensitive. There were a total of 19 reports over the time interval of 1947 to 1983 in the 1998 ACGIH Documentation. In those reports on individuals that were sensitized, the median level was 0.02 ppm of TDI and for those not sensitized the level was 0.01 ppm (Table 2); however, the range in the reports actually overlapped. It is remarkable how steep the dose-response or sharp the threshold is thought to be; there is no apparent margin of safety in this TLV value. The dose response for sensitization to TDI is further illustrated in Table 3 using the data of Wegman et al.24 The level of no response is less than onehalf of the highest value that was used for an adverse effect level; the response shows an effect at 0.0035 ppm which is below the ACGIH TLV and OSHA PEL. One may question whether the TLV and PEL are sufficiently protective. Figure 1 is a graph
Table 2. Studies from which ACGIH Set the TLV for TDI Based on Decrement in PFT* ppm of TDI Sensitized
Not Sensitized
0.003 0.9 0.02†
0.001 0.03 0.01‡
Lowest level Highest level Median level
* Data from a total of 19 reports from the time interval of 1947–1983; mostly grab samples (11). † 7 of 14 reports. ‡ 1 of 5 reports. Table 3. Dose Response for Sensitization to TDI of Workers at Ambient Air Exposures* ppm of TDI in Ambient Air
mL/yr Decline in FEV1
⬍0.002 0.002–0.003 ⬎0.0035
0 42 204
* Data from Wegman et al.24
of these doses on a scale of molecules/m3 of air. This scale was introduced by Rozman et al25 in an analysis of cancer risk assessment but it is excellent to illustrate relative doses to the lungs responsible for occupational asthma. This molecular scale starts on the abscissa with one molecule/m3 (the lowest possible dose). There appears to
be a psychologic barrier, even among physicians and scientists, to the realization that concentrations in ppm and ppb are over a very narrow range and that an enormous number of molecules are still present even at ppb and ppt. This figure shows the steep dose response of the Wegman data in relation to the TLV and PEL (12 ⫻ 1016 molecules/m3 for TDI). Also shown is the minimum concentration (5.6 ⫻ 108 molecules/m3) in the air worldwide calculated above from release from sources in the United States and the decomposition rate of TDI in the atmosphere. The points to be emphasized from Figure 1 are (A) that the dose response is steep for decrements in pulmonary function from TDI, (B) the TLV and PEL for TDI apparently are too high for protection of all workers, and (C) there is obviously a threshold somewhere in the vicinity of 1015 to 1016 molecules/m3 below which asthma may never be seen. HEXAMETHYLENE DIISOCYANATE Table 4 shows the range of doses for the lowest observed adverse effect level (LOAEL) and the no observed adverse effect level (NOAEL) for hexamethylene diisocyanate (HDI) from a survey of the literature by ATSDR26 together with the number of
Table 1. Specific IgE and IgG Levels in Isocyanate Workers Diagnosed with Asthma by PEFR* Asthma by PEFR
Increased IgE Not Increased Increased IgG Not Increased * Data from Kim et al.23
620
Yes
No
3 5 1 7
6 67 8 65
Figure 1. Molecules of TDI per cubic meter of air plotted on the logarithmic molecular scale of Rozman et al25 against the mL per year decline in FEV1 of workers exposed to three levels of TDI in the workplace (data of Wegman et al24). Also indicated on the abscissa is the TLV and PEL (0.005 ppm; 1.2 ⫻ 1017 molecules/m3) and the minimum worldwide concentration in air of TDI (5.6 ⫻ 108 molecules/m3); see text for calculation.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Table 4. Range of Doses for Adverse Respiratory Effects in Humans for Hexamethylene Diisocyanate* ● Lowest observed adverse effect level: 0.006 ppm to 0.0001 ppm (1.5 ⫻ 100,000,000,000,000,000 molecules/m3 to 2.4 ⫻ 1,000,000,000,000,000 molecules/m3) ● No observed adverse effect level: 0.0006 ppm (1.5 ⫻ 10,000,000,000,000,000 molecules/m3) * Calculated from data of ATSDR Toxicological Profile.26
molecules/m3 in air for each of these concentrations. When expressed as numbers of molecules, the steep doseresponse curve and the overlap between the LOAEL and NOAEL are apparent. Figure 2 shows these data plotted on the logarithmic molecular scale of Rozman et al.25 This visualization further emphasizes the narrow range over which concentrations are assessed for regulatory and causation purposes. FORMALDEHYDE The ACGIH Ceiling for formaldehyde is 0.3 ppm (0.37 mg/m3) and the OSHA PEL is 0.75 ppm (0.92 mg/m3). Note that 0.37 mg/m3 is 7.4 ⫻ 1018 molecules/m3. It is clearly impossible to avoid formaldehyde. Indeed, formaldehyde is an essential compound in intermediary metabolism of all animals and plants. The concentration in the blood of normal, healthy humans is 2.6 ppm.27 It can be calculated that 58 g are produced daily in intermediary metabolism in adult humans.7 The concentration in mainstream cigarette smoke ranges from 47 to 214 ppm.28 There are, however, at least five studies29 –33 that show no adverse effect of formaldehyde on asthmatics at concentrations of about 3 ppm. The original report by Hendrick and Lane34 on formaldehyde-induced asthma in nurses working in a renal dialysis unit was the consequence of heavy exposure to formaldehyde for many years. This report generated unwarranted, speculative extrapolation of asthma in individuals exposed to much lower concentrations. There are no reliable reports of asthma being produced in individuals at levels anywhere near the TLV or PEL; those values were set by
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these agencies at the very minimal irritation levels for conjunctiva and nasal epithelium and partially in response to the formaldehyde fears of the 1980s. One should certainly not confuse the TLV and PEL for formaldehyde as levels at or even above which one might induce asthma. The TLV and PEL for formaldehyde are in contrast to the TLV and PEL for TDI and HDI. There is an overlap of these regulatory values for the diisocyanates with concentrations reported in the literature that have adverse effects on pulmonary function. For formaldehyde, there is a generous margin of safety for this ubiquitous and essential compound. The message to be made is that TLVs and PELs may or may not offer a margin of safety. The practicing physician cannot accept these values with the degree of trust one would like. Unfortunately, further information may be needed for a conclusion of causality.
ADDITIVE EFFECTS The question always arises about additive effects from mixtures of chemicals. The ACGIH (Table 5) provides a formula for calculating additive effects when the substances act on the same organ system, presumably by the same mechanism. Also included in the Table is the formula for calculating the permissible TLV concentration when the effects are independent, ie, act on different organs by presumably different mechanisms. Again the decision on the effect of mixtures can be difficult and may require consultation with one quite knowledgeable about the chemicals involved. In conclusion, occupational asthma has been associated with many agents of diverse structures. Some of these associations may be due to allergic mechanisms but for many of them the allergic mechanism has not been demonstrated. For the isocyanates, which are probably the most common cause of occupational asthma, an allergic mechanism has not been conclusively demonstrated for inducing asthma. The TLV and PEL for isocyanates may not be protective for all workers. The concentrations observed to have an effect, or no effect, are all in a very narrow range. For formaldehyde, the original report of asthma in nurses working in a renal dialysis unit engendered an extrapolation to doses lower than neces-
Figure 2. Molecules of HDI per cubic meter of air plotted on the logarithmic molecular scale of Rozman et al.25 Indicated on the abscissa are the range of values for the LOAEL and the NOAEL reported in the ATSDR Toxicological Profile26 for HDI.
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Table 5. ACGIH Position on Mixtures* ● Additive effects (“substances which act upon the same organ system”) C1/TLV1 ⫹ C2/TLV2 ⫹ C3/TLV3 ⫹ . . . ⫽ 1 ● Independent effects (“purely local effects on different organs of the body”) C1/TLV1 ⫽ 1; C2/TLV2 ⫽ 1; C3/TLV3 ⫽ 1; etc.
20.
* Formulas from ACGIH.14
21.
sary to prevent occupational asthma. Current limits in industry on formaldehyde provide a wide safety margin for formaldehyde in the production of occupational asthma. Finally, it should be recognized that a zero concentration for any substance in air is probably unobtainable and indeed even unnecessary. Fortunately, however, it is probably not necessary to have a concentration of zero for any chemical because dose-response information suggests there is a threshold of many molecules per liter of inhaled air at which there is no response. ACKNOWLEDGMENT The author expresses his grateful appreciation to Dr. Laszlo Kerecsen for preparation of the figures expressing dosage on a molecular scale. REFERENCES 1. Bernstein DI. Allergic reactions to workplace allergens. JAMA 1997;278: 1907–1913. 2. Chan-Yeung M. Occupational asthma. Chest 1990;98(Suppl):148S–161S. 3. Chan-Yeung M. Occupational asthma. Environ Health Perspect 1995; 103(Suppl 6):249 –252. 4. Newman LS. Occupational asthma— diagnosis, management, and prevention. Clin Chest Med 1995;16: 621– 636. 5. HSDB (Hazardous Substances Data Bank) [TOXNET database online]. http: //toxnet.nlm.nih.gov/servlets.simplesearch?1.5.1.367. Bethesda, Maryland: National Library of Medicine. 6. MEDLINE (database online). Bethesda, Maryland: National Library of Medicine. 7. Sullivan JB, Krieger GR, eds. Hazardous materials toxicology. Clinical principles of environmental health. Baltimore: Williams & Wilkins, 1992. 8. Ellenhorn MJ. Ellenhorn’s medical toxicology: diagnosis and treatment of
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subjects with asthma. Environ Res 1984;35:133–139. 31. Green DJ, Sauder LR, Kulle TJ, Bascom R. Acute response to 3.0 ppm formaldehyde in exercising healthy nonsmokers and asthmatics. Am Rev Respir Dis 1987;135:1261–1266.
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32. Uba G, Pachorek D, Bernstein J, et al. Prospective study of respiratory effects of formaldehyde among healthy and asthmatic medical students. Am J Ind Med 1989;15:91–101. 33. Witek TJ Jr, Schachter EN, Tosun T, et al. An evaluation of respiratory effects
following exposure to 2.0 ppm formaldehyde in asthmatics: lung function, symptoms, and airway reactivity. Arch Environ Health 1987;42:230 –237. 34. Hendrick DJ, Lane DJ. Formalin asthma in hospital staff. Brit Med J 1975;1:607– 608.
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