JOURNAL OF APPLIED TOXICOLOGY, VOL. 12(4), 305-306 (1992)
LETTERS TO THE EDITOR
Erythrocyte and Tissue AChE Lnhibition G. B. Koelle School of Medicine, Department of Pharmacology, University of Pennsylvania, 36th Street and Hamilton Walk. Philadelphia, P A 19104-6084, USA
The question has arisen as to whether the degree of inhibition of the acetylcholinesterase (AChE) activity of the erythrocytes in the peripheral circulation serves as a reliable index of the degree of inhibition of the AChE of the central nervous system or of the peripheral nervous system and effector organs. It does not. Immediately following exposure, the amount of anticholinesterase (anti-ChE) agent, of either the irreversible organophosphate or ‘reversible’ type, that penetrates various tissues will depend on a number of physiological factors and on the chemical characteristics of the agent. In the former category are the relative velocity of the circulation in various organs and their total blood supply, their fat, protein and water contents and the permeability of the various capillary beds. In the latter are the degree of water/fat solubility, the degree of ionization and the molecular weight and
other characteristics of the agent. As an extreme example, practically none of a quaternary compound will penetrate the blood-brain barrier to reach the central nervous system. With the passage of time, in hours or days following exposure, the problem becomes even more complicated because of the different rates of regeneration of AChE in various tissues. Following exposure to an irreversible organophosphorus anti-ChE agent, the rate of regeneration of AChE in the erythrocytes will depend on the rate of erythropoiesis (120 days in human beings and about one-tenth this figure in rats). In most tissues, AChE regenerates at intermediate but variable rates. Thus, although the AChE of the tissues and the erythrocytes appears to be identical, the degree of inhibition of the former does not provide an indication of that of the latter.
Indoor Air Quality Michael R. Greenwood Liquid Imaging Materials Association. c/o Xerox Corporation, Building 0843-168, 800 Salt Road, Webster, NY 14580. USA.
The Liquid Imaging Materials Association (LIMA) is an ‘Industry Work Group’ that has been following the development of proposals related to indoor air standards and is concerned that all volatile organic compounds (VOCs) of widely varying toxicity will be encapsulated in one generic standard. The members of the Association have gathered together and published toxicity data related to the isoparaffinic hydrocarbons. Recently, the Occupational Safety and Health Administration (OSHA) made a request for information on ‘Occupational Exposure to Indoor Air Pollutants’. The LIMA responded specifically to one item: Monitoring and Exposure Assessment-[26] (a) Is there any evidence to suggest that indoor air quality (IAQ)
0 1992 by John Wiley & Sons, Ltd.
complaints coincide with specific amounts of specific volatile organic chemicals (VOCs) in air? That is, can VOCs in mg m-3 be used as a measure of IAQ? ~~
LIMA RESPONSE TO OSHA
There is strong evidence against lumping all volatile organics into one generic group called VOCs and setting an all-encompassing IAQ standard. In a paper published by Mullin et ~ 1the. toxicity ~ of the isoparaffinic hydrocarbons was well documented and sensory irritation data reported. The report indicated that no
306
LETTERS TO T H E EDITOR
effects were seen on the respiratory rate. and sensory irritation was not produced in mice at 1834 mg m-3 (-300 ppm) or 2621 mg m-> (-420 ppm), using an ASTM E 981 modified Greenwood’ at the Indoor Air ‘90 meeting in Toronto discussed the Molhave6.’ data that indicated concerns of sensory irritation at levels of VOCs above 1 ppm. Support for these data was given by Tucker,x who recommends that ‘organic vapors from any single source should be limited at 0.5 mg m P , Seifert,” who suggests a target guideline for VOCs intended to be applicable to the non-industrial indoor environments, such as offices, schools, etc., of 0.3 mg mP3(which equates to 0.05 ppm for isoparaffinic hydrocarbons), and Tsuchiya, who only gives measurements and does not comment on health-associated topics but justifies his analysis of VOCs in buildings, associated with the use of liquid imaging processes, based on Molhave’s recommendations. All of these authors referenced the Molhave data unchallenged. None of the authors took into account the make-up of the Molhave 22-member ‘cocktail‘, of which 80% is comprised of toluene and butyl acetate. In fact, when the experiment was repeated by Otto et al.”.” they only confirmed Molhave’s data and once again did not address the issue of the cocktail components. However. unlike the original Danish studies by Molhave. an extensive battery of neurobehavioral tests was used to characterize what aspects of cognitive function, if any, were affected by VOC exposure. Otto et al. found no effect on any of five memory tests using VOC mixtures up to 25 mg mP3. Perhaps, as was suggested by Otto ef al.,” it would be better to first understand the lowlevel sensory irritation associated with these two components rather than assume that all components have the same low-level sensory irritation potential or that the results can be applied across the board to all vocs. Even allowing for an order of magnitude safety
factor for low-level sensory irritation. the isoparaffinic hydrocarbons should be safe at 30 ppm. This level certainly is below the level at which any discomfort was reported (53 ppm) in a human test group.’ Furthermore, Mullin’ reported that the odor was imperceptible at 22 ppm. We would therefore suggest that the use of Molhave’s data. which are based on a mixture of a limited group of volatile organics, is not justified since two of the chemicals constitute 80% of the mixture and could be responsible for the low-level sensory effects. A literature search did not indicate that the potential for either or both of these VOCs being responsible for the lowlevel sensory irritation has been properly addressed. Certainly the clearly documented toxicity of the isoparaffinic hydrocarbons would indicate that the toxicity of individual VOCs should be considered. Molhave’s cocktail on which much of the indoor air pollution for VOCs is based is a better indication of the low-level sensory irritation of toluene and butyl acetate than of chemicals not even present in the cocktail.
CONCLUSION Based on the above information it is concluded that VOCs in mg m ’ cannot be used to effectively measure IAQ. This is because of the widely varying toxicity of the different VOCs and the failure to identify individual component VOCs responsible for the low-level sensory irritation levels caused by the Molhave cocktail. Furthermore, in spite of the EPA repeating the Molhave experiments, the EPA did not address the issue of the cocktail components. The extensive toxicity studies on isoparaffinic hydrocarbons reported by Mullin et al. did not show the 5ame effects as were found with the Molhave cocktail used in both his and Otto’s experiments.
REFERENCES
1. Occupational Health and Safety Administration, Request for information on ‘Occupational Exposure to Indoor Air Pollutants‘, 29 CFR Part 1910. Fed. Reg. 56(183), 47892-47897 (1991). 2. L. S. Mullin, A. W. Ader, W. C. Daughtrey, D. 2. Frost and M. R. Greenwood, Toxicology update on isoparaffinic hydrocarbons: a summary of physical properties, toxicity studies and human exposure data. J. Appl. Toxicol. 10, 135142 (1990). 3. American Society for Testing and Materials (ASTM), Standard E-981-84. ASTM, Philadelphia, PA (1985). 4. Y . Alarie, Dose response analysis in animal studies: prediction of human responses. Environ. Health. Perspect. 42, 9-13 (1981). 5. M. R. Greenwood, The toxicity of isoparaffinic hydrocarbons and current exposure practices in the non-industrial (office) indoor air environment. Proceedings of lndoor Air ‘90, Distributed by International Conference on Indoor Air Quality And Climate, Inc. 2344 Haddington Crescent, Ottawa, Ontario K I H 8J4 Canada. Vol. 5, pp. 169-175 (1990). 6. L. Molhave, Volatile organic compounds as indoor air pollutants. Indoor air and human health. Proceedings of the Seventh Life Sciences Symposium, Knoxville, Tennessee, Edited by R. B. Gammeage, S. V. Kaye and V. A. Jacobs: Lewis Publishers, Inc. 121 S.Main St, Chelsea, MI 48118. pp. 403-414 (1984). 7. L. Molhave, E. Each and 0. F. Pedersen, Human reactions
8.
9.
10.
11.
12.
to low concentratiom of volatile organic compounds. Environ. Int. 12, 167-175 (1986). W. G. Tucker, Building with low-emitting materials and products: where do we stand? Proceedings of lndoor Air ’90, Distributed by International Conference on Indoor Air Quality And Climate, Inc. 2344 Haddington Crescent, Ottawa, Ontario K1H 8J4 Canada. Vol. 3, pp. 251-256 (1990). B. Seifert, Regulating indoor air. Proceedings of lndoor Air ’90, Distributed by International Conference on Indoor Air Quality And Climate, Inc. 2344 Haddington Crescent, Ottawa, Ontario K I H 8J4 Canada. Vol. 5, pp. 35-49 (1990). Y . Tsuchiya and J. E. Stewart, Volatile organic compounds in the air of Canadian buildings with special reference to wet process photocopying machines. Proceedings of Indoor Air ’90, Distributed by International Conference on Indoor Air Quality And Climate, Inc. 2344 Haddington Crescent, Ottawa, Ontario K1H 8J4 Canada. Vol. 2, pp. 633-638 (1990). D. A. Otto, L. Molhave, G. Rose, H. K. Hudnell and D. House, Neurotoxic Effects of Controlled Exposure to a Complex Mixture of Volatile Organic Compounds. Report to the EPA under Contracts 68-02-4179 and 68-02-3800. EPA Report 60011-90-001. Health Effects Research Laboratory, Research Triangle Park, NC (1990). D. A. Otto, L. Molhave, G. Rose, H. K. Hudnell and D. House, Neurobehavioral and Sensory Irritant Effects of Controlled Exposure to a Complex Mixture o f Volatile Organic Compounds. Neurotox. Teratol. 12, pp. 649-652 (1990).
LETTERS TO THE EDITOR
Erythrocyte and Tissue AChE Lnhibition G. B. Koelle School of Medicine, Department of Pharmacology, University of Pennsylvania, 36th Street and Hamilton Walk. Philadelphia, P A 19104-6084, USA
The question has arisen as to whether the degree of inhibition of the acetylcholinesterase (AChE) activity of the erythrocytes in the peripheral circulation serves as a reliable index of the degree of inhibition of the AChE of the central nervous system or of the peripheral nervous system and effector organs. It does not. Immediately following exposure, the amount of anticholinesterase (anti-ChE) agent, of either the irreversible organophosphate or ‘reversible’ type, that penetrates various tissues will depend on a number of physiological factors and on the chemical characteristics of the agent. In the former category are the relative velocity of the circulation in various organs and their total blood supply, their fat, protein and water contents and the permeability of the various capillary beds. In the latter are the degree of water/fat solubility, the degree of ionization and the molecular weight and
other characteristics of the agent. As an extreme example, practically none of a quaternary compound will penetrate the blood-brain barrier to reach the central nervous system. With the passage of time, in hours or days following exposure, the problem becomes even more complicated because of the different rates of regeneration of AChE in various tissues. Following exposure to an irreversible organophosphorus anti-ChE agent, the rate of regeneration of AChE in the erythrocytes will depend on the rate of erythropoiesis (120 days in human beings and about one-tenth this figure in rats). In most tissues, AChE regenerates at intermediate but variable rates. Thus, although the AChE of the tissues and the erythrocytes appears to be identical, the degree of inhibition of the former does not provide an indication of that of the latter.
Indoor Air Quality Michael R. Greenwood Liquid Imaging Materials Association. c/o Xerox Corporation, Building 0843-168, 800 Salt Road, Webster, NY 14580. USA.
The Liquid Imaging Materials Association (LIMA) is an ‘Industry Work Group’ that has been following the development of proposals related to indoor air standards and is concerned that all volatile organic compounds (VOCs) of widely varying toxicity will be encapsulated in one generic standard. The members of the Association have gathered together and published toxicity data related to the isoparaffinic hydrocarbons. Recently, the Occupational Safety and Health Administration (OSHA) made a request for information on ‘Occupational Exposure to Indoor Air Pollutants’. The LIMA responded specifically to one item: Monitoring and Exposure Assessment-[26] (a) Is there any evidence to suggest that indoor air quality (IAQ)
0 1992 by John Wiley & Sons, Ltd.
complaints coincide with specific amounts of specific volatile organic chemicals (VOCs) in air? That is, can VOCs in mg m-3 be used as a measure of IAQ? ~~
LIMA RESPONSE TO OSHA
There is strong evidence against lumping all volatile organics into one generic group called VOCs and setting an all-encompassing IAQ standard. In a paper published by Mullin et ~ 1the. toxicity ~ of the isoparaffinic hydrocarbons was well documented and sensory irritation data reported. The report indicated that no
306
LETTERS TO T H E EDITOR
effects were seen on the respiratory rate. and sensory irritation was not produced in mice at 1834 mg m-3 (-300 ppm) or 2621 mg m-> (-420 ppm), using an ASTM E 981 modified Greenwood’ at the Indoor Air ‘90 meeting in Toronto discussed the Molhave6.’ data that indicated concerns of sensory irritation at levels of VOCs above 1 ppm. Support for these data was given by Tucker,x who recommends that ‘organic vapors from any single source should be limited at 0.5 mg m P , Seifert,” who suggests a target guideline for VOCs intended to be applicable to the non-industrial indoor environments, such as offices, schools, etc., of 0.3 mg mP3(which equates to 0.05 ppm for isoparaffinic hydrocarbons), and Tsuchiya, who only gives measurements and does not comment on health-associated topics but justifies his analysis of VOCs in buildings, associated with the use of liquid imaging processes, based on Molhave’s recommendations. All of these authors referenced the Molhave data unchallenged. None of the authors took into account the make-up of the Molhave 22-member ‘cocktail‘, of which 80% is comprised of toluene and butyl acetate. In fact, when the experiment was repeated by Otto et al.”.” they only confirmed Molhave’s data and once again did not address the issue of the cocktail components. However. unlike the original Danish studies by Molhave. an extensive battery of neurobehavioral tests was used to characterize what aspects of cognitive function, if any, were affected by VOC exposure. Otto et al. found no effect on any of five memory tests using VOC mixtures up to 25 mg mP3. Perhaps, as was suggested by Otto ef al.,” it would be better to first understand the lowlevel sensory irritation associated with these two components rather than assume that all components have the same low-level sensory irritation potential or that the results can be applied across the board to all vocs. Even allowing for an order of magnitude safety
factor for low-level sensory irritation. the isoparaffinic hydrocarbons should be safe at 30 ppm. This level certainly is below the level at which any discomfort was reported (53 ppm) in a human test group.’ Furthermore, Mullin’ reported that the odor was imperceptible at 22 ppm. We would therefore suggest that the use of Molhave’s data. which are based on a mixture of a limited group of volatile organics, is not justified since two of the chemicals constitute 80% of the mixture and could be responsible for the low-level sensory effects. A literature search did not indicate that the potential for either or both of these VOCs being responsible for the lowlevel sensory irritation has been properly addressed. Certainly the clearly documented toxicity of the isoparaffinic hydrocarbons would indicate that the toxicity of individual VOCs should be considered. Molhave’s cocktail on which much of the indoor air pollution for VOCs is based is a better indication of the low-level sensory irritation of toluene and butyl acetate than of chemicals not even present in the cocktail.
CONCLUSION Based on the above information it is concluded that VOCs in mg m ’ cannot be used to effectively measure IAQ. This is because of the widely varying toxicity of the different VOCs and the failure to identify individual component VOCs responsible for the low-level sensory irritation levels caused by the Molhave cocktail. Furthermore, in spite of the EPA repeating the Molhave experiments, the EPA did not address the issue of the cocktail components. The extensive toxicity studies on isoparaffinic hydrocarbons reported by Mullin et al. did not show the 5ame effects as were found with the Molhave cocktail used in both his and Otto’s experiments.
REFERENCES
1. Occupational Health and Safety Administration, Request for information on ‘Occupational Exposure to Indoor Air Pollutants‘, 29 CFR Part 1910. Fed. Reg. 56(183), 47892-47897 (1991). 2. L. S. Mullin, A. W. Ader, W. C. Daughtrey, D. 2. Frost and M. R. Greenwood, Toxicology update on isoparaffinic hydrocarbons: a summary of physical properties, toxicity studies and human exposure data. J. Appl. Toxicol. 10, 135142 (1990). 3. American Society for Testing and Materials (ASTM), Standard E-981-84. ASTM, Philadelphia, PA (1985). 4. Y . Alarie, Dose response analysis in animal studies: prediction of human responses. Environ. Health. Perspect. 42, 9-13 (1981). 5. M. R. Greenwood, The toxicity of isoparaffinic hydrocarbons and current exposure practices in the non-industrial (office) indoor air environment. Proceedings of lndoor Air ‘90, Distributed by International Conference on Indoor Air Quality And Climate, Inc. 2344 Haddington Crescent, Ottawa, Ontario K I H 8J4 Canada. Vol. 5, pp. 169-175 (1990). 6. L. Molhave, Volatile organic compounds as indoor air pollutants. Indoor air and human health. Proceedings of the Seventh Life Sciences Symposium, Knoxville, Tennessee, Edited by R. B. Gammeage, S. V. Kaye and V. A. Jacobs: Lewis Publishers, Inc. 121 S.Main St, Chelsea, MI 48118. pp. 403-414 (1984). 7. L. Molhave, E. Each and 0. F. Pedersen, Human reactions
8.
9.
10.
11.
12.
to low concentratiom of volatile organic compounds. Environ. Int. 12, 167-175 (1986). W. G. Tucker, Building with low-emitting materials and products: where do we stand? Proceedings of lndoor Air ’90, Distributed by International Conference on Indoor Air Quality And Climate, Inc. 2344 Haddington Crescent, Ottawa, Ontario K1H 8J4 Canada. Vol. 3, pp. 251-256 (1990). B. Seifert, Regulating indoor air. Proceedings of lndoor Air ’90, Distributed by International Conference on Indoor Air Quality And Climate, Inc. 2344 Haddington Crescent, Ottawa, Ontario K I H 8J4 Canada. Vol. 5, pp. 35-49 (1990). Y . Tsuchiya and J. E. Stewart, Volatile organic compounds in the air of Canadian buildings with special reference to wet process photocopying machines. Proceedings of Indoor Air ’90, Distributed by International Conference on Indoor Air Quality And Climate, Inc. 2344 Haddington Crescent, Ottawa, Ontario K1H 8J4 Canada. Vol. 2, pp. 633-638 (1990). D. A. Otto, L. Molhave, G. Rose, H. K. Hudnell and D. House, Neurotoxic Effects of Controlled Exposure to a Complex Mixture of Volatile Organic Compounds. Report to the EPA under Contracts 68-02-4179 and 68-02-3800. EPA Report 60011-90-001. Health Effects Research Laboratory, Research Triangle Park, NC (1990). D. A. Otto, L. Molhave, G. Rose, H. K. Hudnell and D. House, Neurobehavioral and Sensory Irritant Effects of Controlled Exposure to a Complex Mixture o f Volatile Organic Compounds. Neurotox. Teratol. 12, pp. 649-652 (1990).
