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Update of the 1993 database of Schaper for RD50 and corresponding TLV values*

DOI: https://doi.org/10.22427/NTP-DATA-022-00004-0002-000-0

Inhalation Threshold Limit Values (TLVs) for 103 chemicals originally listed in Schaper, M. (1993), Development of a database for sensory irritants and its use in establishing occupational exposure limits, Am. Ind. Hyg. Assoc. J. 54: 488-544; doi: 10.1080/15298669391355017, were updated in 2015. Data resulting from this update are included in this data table.

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ID Number Chemical Name A,B Notes and Synonyms CASRN Updated TLV Reference Date Mouse StrainE Exposure Details ReferenceC RD50 (ppm) RD50 X 0.03 (ppm) Mean RD50 X 0.03 (ppm) 1993 TLV-TWA or TLV Ceiling (ppm) 2015 TLV-TWA, TLV Ceiling, or STEL(s) (ppm) 2015 TLV BasisD

*Inhalation Toxicology Databases in Mice for QSAR and Safe Levels of Exposure for Humans

INTRODUCTION

Reported cited published

Two data tables are provided as database required to establish a Quantitative Structure-Activity Relationship (QSAR). The first table, Inhalation TLV 1993 Update, was updated from the database published by Schaper (1) in 1993. This table was used to prepare a QSAR. The second table, Inhalation TLV 2015 ACGIH, (https://manticore.niehs.nih.gov/datasets/search/2015-acgih-tlvs) is a table of TLVs from a 2015 booklet (2) by the American Conference of Governmental Industrial Hygienists (ACGIH). It was used to evaluate the predictivity of the prepared QSAR. It contains 112 chemicals for separate testing. A database published in 1998, Alarie et al. (3), is available for consultation in the preparation of a new QSAR. This 1998 database was used by Gupta et al. (4) to prepare a QSAR, also available for consultation.

  1. Can results obtained in mice provide estimates of safe levels of exposure for humans to volatile organic chemicals (VOCs) of industrial importance?

Schaper’s 1993 table (1) was updated, listing the potency in mice for 89 chemicals, potencies calculated as RD50s. In this Table the available respective “safe level of exposure in humans” known as Threshold Limit Values (TLVs) are listed. These are published yearly by the American Conference of Governmental Industrial Hygienists (ACGIH) since 1946. Such values published in 1968 became the Permissible Exposure Levels (PELs) when the Occupational Health and Safety Act (OSHA) became law for the US in 1970.

A linear regression analysis was conducted using a fraction of each listed RD50 value, 0.03 x RD50, vs their respective TLV values of 1991-1992, as listed in Schaper’s table. The table, updated in 2015, also lists additional RD50s as well as updating of their respective TLVs to 2015.

Excellent correlations were found between the potencies in mice (0.03 x RD50s) and TLVs and were presented in a Lecture at the Society of Toxicology Meeting in 2016. Scientists interested in using Table 1, can listen to this Lecture for information and results with this bioassay at this link: https://vimeo.com/163860403

  1. Can Quantitative Structure-Activity Relationships (QSAR) be obtained to estimate RD50s and therefore TLVs or PELs?

In 1998, a table was published by Alarie et al. (3), now containing 145 VOCs. They were divided in nonreactive VOCs (nrVOCs) and reactive VOCs (rVOCs). The physicochemical descriptors published by M. H. Abraham were used to estimate the potency (RD50) of these VOCs. As shown in this article we were able to estimate RD50 of nrVOCs but not for rVOCs.

  1. In 2015, Gupta et al. (4) published an article using the same database published in 1998, noted above. They also used physicochemical descriptors but they added chemical reactivity descriptors. As a result, they were able to estimate RD50s for both nrVOCs and rVOCs using statistical and QSAR procedures. This progress was also presented, and discussed, at the Lecture noted above.
  2. With the data then available, an answer was prepared for NTP/NIEHS’ request for data. This answer stated that if a QSAR was to be used for “regulatory purposes” there would be a need to supply the regulator with an estimate of the possible deviation from the estimated values of RD50 for a new chemical, i.e. how good is the predictivity of this QSAR. In order to obtain this, the ACGIH 2015 Inhalation TLVs: “Table 2 List of chemicals with TLVs but with no RD50 values…..”, was included in the information submitted. How it can be used was presented and discussed here: https://ntp.niehs.nih.gov/iccvam/pubcomment/fr-2016-16840/alarie-508.pdf and also available and discussed here: https://vimeo.com/163860403

This dataset was prepared for scientists interested in QSAR in Toxicology. The two tables provide for easy access to a specific inhalation toxicity database as well as how it can be used, for in-silico methods to proceed. Basically, we need:

1) reliable animal bioassay with potency numbers from a concentration-response relationship;

2) reliable human “safe level of exposure” numbers;

3) good correlation between the animal bioassay potency and safe level of exposure in humans;

4) good physicochemical and chemical reactivity descriptors;

5) good equation to estimate potency using the descriptors for a new chemical;

6) good estimates of the variability in potency (RD50s) calculated using the QSAR procedure, so that regulators can have confidence that such estimates can be used for “safe level of exposure” for humans.

References

  1. Schaper, M. (1993). Development of a database for sensory irritants and its use in establishing occupational exposure limits. Am. Ind. Hyg. Assoc. J. 54: 488-544.    https://doi.org/10.1080/15298669391355017
  2. Booklet of The American Conference of Governmental Industrial Hygienists (2015). TLVs and BEIs Based on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents & Biological Exposure Indices.
  3. Alarie, Y., Schaper, M., Nielsen G.D. and Abraham, M.H. (1998). Structure-Activity relationships of volatile organic chemicals as sensory irritants. Arch. Toxicol. 72: 125-140. https://doi.org/10.1007/s002040050479
  4. Gupta, S., Basant, N. and Singh, K.P. (2015). Estimating sensory irritation potency of volatile organic chemicals using QSARs based on decision tree methods for regulatory purpose. Ecotoxicology 24: 873-886. https://doi.org/10.1007/s10646-015-1431-y

Footnotes

A  Chemicals with RD50 values obtained in male mice of various strains (except for acrolein, acetic acid and sulfur dioxide obtained in both male and female mice) and for which a TLV value has been established to primarily prevent sensory irritation in exposed workers. Update includes all chemicals from Schaper, 1993, with additions from Nielsen et al., 2007, Dudek et al., 1992 and Alarie et al., 1980, References 1, 2, 8 and 9 respectively and given for each chemical in the Table above.

The 2015 TLV value and basis for each chemical listed were obtained from the American Conference of Governmental Industrial Hygienists (ACGIH) as given in Reference 3.

The 1991-992 TLV values listed in the 1993 Schaper database are also listed here for comparison with the 2015 values.

RD50 was originally defined from a dose-response from linear regression analysis to be the dose required to elicit a 50% decrease in respiratory rate in mice as given in reference 4. It should have been defined "exposure concentration-response" instead of "dose-response" as given in Reference 10 when it became a standard method with ASTM. RD50 is not applicable to any other type of decrease such as a decrease in tidal volume, minute volume, decrease in expiratory airflow, etc. It is only applicable when a definite lengthening of the expiratory phase is observed due to a pause after inspiration and not due to airflow limitation during expiration or pauses between breaths observed during pulmonary irritation, see references 4, 6, 7 and for details.  Also note that in some of the figures in reference 4 the polarity of the signal is not always consistent; one example is the correct polarity (upward deflection during inspiration) for mouse 1 in Figure 23 while it is inverted for mouse 2 in this same Figure.

RD50 has been appropriately measured in a variety of mice strains of different sensitivities as shown in Table 1 and References 1 and 9 by different investigators.

Nothing is known about quantitative extrapolations to humans when using other animal species were used as discussed at http://rd50.com/   or  http://www.yvesalarie.com/ or http://www.pitt.edu/~rd50/

Discussions regarding the influence of exposure durations and other factors possibly affecting RD50 values can also be found in references 1, 5, 9 and 11. Reference 5 also presents relationships between lowest observed adverse effect levels (LOAELs) and acute reference exposure levels (RELs) of human responses to sensory irritants and RD50s.

The computerized method described in References 7 and 11 has now been widely used to evaluate a variety of single airborne chemicals as well as diverse mixtures of airborne chemicals. It has also been used for mouse and rat asthma models (reference 15). It provides a better evaluation when complex effects are elicited at different levels of the respiratory tract, particularly when evaluating mixtures, as described in Reference 12 and more recently for nanoparticles (Reference 16). The software for the computerized method is commercially available and runs on Windows.

B  Chemical names as listed in Reference 1, name in parenthesis as now listed in Reference 3.

Note: A total of 12 new chemicals with RD50 values were added to the 1993 Schaper database

Note: A total of 12 new entries of RD50 values were added to chemicals already listed in the 1993 Schaper database

Note: For sulfur dioxide the RD50 values are listed for 9 different types of mice, male and female, some measured in the same laboratory for a total of 15 values, see Reference 9, as well as for one other type of mouse from Schaper database which is also included with the other listed values.  The entries for sulfur dioxide illustrate the different sensitivities with different types of mice. There is a factor of 10 between the most and least sensitive and the SW type (the type originally used) is in the middle.

Note: Inorganic chemicals are also listed and noted as well as a few evaluated as airborne aerosols.

C For each chemical, the published RD50 value can be found in References 1, 2, 8 or 9 thus details of exposures, exposure durations, how the RD50 value was calculated, etc. can be obtained.

D   Abbreviations as listed by ACGIH in reference 3: Eye & URT irr = Eye and upper respiratory tract irritation; CNS = central nervous system; PNS peripheral nervous system; dam = damage; repro = reproductive; LRT irr = lower respiratory tract irritation; Resp sens = respiratory sensitization; GI = gastrointestinal; irr = irritation

E Strain denoted with "(F)" are female

References

1.      Schaper, M. (1993). Development of a database for sensory irritants and its use in establishing occupational exposure limits. Am. Ind. Hyg.  Assoc. J. 54: 488-544 , PMID: 8379496, DOI: 10.1080/15298669391355017

2.      Nielsen, G.D., Wolkoff, P. and Alarie, Y. (2007). Sensory irritation: Risk assessment approaches. Reg. Toxicol. Pharmacol. 48: 6-18, PMID: 17241726, DOI: 10.1016/j.yrtph.2006.11.005

3.      Booklet of The American Conference of Governmental Industrial Hygienists (ACGIH) (2015). TLVs and BEIs Based on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents & Biological Exposure Indices

4.      Alarie, Y. (1966). Irritating properties of airborne materials to the upper respiratory tract. Arch. Environ. Health 13:433-449, PMID: 5921282,

5.      Kuwabara, Y., Alexeeff, V., Broadwin, R. and Salmon, A.G. (2007). Evaluation and application of the RD50 for determining acceptable exposure levels of airborne sensory irritants for the general public. Environ. Health Perspec. 115: 1609-1616, PMID: 18007993, DOI: 10.1289/ehp.9848

6.      Vijayaraghavan, R., Schaper, M., Thompson, R., Stock, M.F. and Alarie, Y. (1993). Characteristic modifications of the breathing pattern of mice to evaluate the effects of airborne chemicals on the respiratory tract. Arch. Toxicol. 67: 478-490, PMID: 8239997,

7.      Vijayaraghavan, R., Schaper, M., Thompson, R., Stock, M.F., Boylstein, L.A., Luo, J.E. and Alarie, Y. (1994). Computer assisted recognition and quantitation of the effects of airborne chemicals acting at different areas of the respiratory tract in mice. Arch. Toxicol. 68: 434-443, PMID: 7802589,

8.      Dudek, B.R., Short, R.D., Brown, M.A., and Roloff, M.W.  (1992). Structure-activity relationship of a series of sensory irritants. J. Toxicol. Environ. Health 37: 511-518, PMID: 1464906, DOI: 10.1080/15287399209531689

9.      Alarie, Y., Kane, L. and Barrow, C. (1980). Sensory irritation: The use of an animal model to establish acceptable exposure to airborne chemical irritants. In: Toxicology: Principles and Practice. Reeves, A.L. (Ed.), John Wiley & Sons. p. 48-92

10.   ASTM E981-19, Standard Test Method for Estimating Sensory Irritancy of Airborne Chemicals, ASTM International, West Conshohocken, PA, 2019. DOI: 10.1520/E0981-19

11.  Alarie, Y., Nielsen, G.D. and Schaper, M.M. (2000). Animal bioassays for evaluation of indoor air quality. In: Indoor Air Quality Handbook. Spengler, J.D., Samet, J.M. and McCarthy, J.F. Eds. McGraw-Hill, NY. p. 23.1-23.49

12.  Alarie, Y. (2000). Computerized animal bioassay to evaluate the effects of airborne chemicals on the respiratory tract. In: Indoor Air Quality Handbook. Spengler, J.D., Samet, J.M. and McCarthy, J.F. Eds. McGraw-Hill, NY. p. 24.1-24.25

13.  De Ceaurriz, J., Gagnaire, F., Ban, M. and Bonnet, P. (1988). Assessment of the relative hazard involved with airborne irritants with additional hepatotoxic or nephrotoxic properties in mice. J. Appl. Toxicol. 8: 417-422, PMID: 2852685,

14.   Nielsen, G.D., Hougard, K.S., Larsen, S.T., Hammer, Wolkoff, P., Clausen, P.A., Wilkins, C.K. and Alarie, Y. (1999). Acute effects of formaldehyde and ozone in BALB/c mice. Human and Experimental Toxicol. 18: 400-409, PMID: 10413245, DOI: 10.1191/096032799678840246

15.  Hoyman, H.-G. (2012) Lung function measurements in rodents in pharmacology studies. Frontiers in Toxicology 3: 1-11

16.  Leppänen, M., Korpi, A., Yli-Pirila, P., Lehto, M., Wolff, H., Kosma, V-M., Alenius, H. and Pasanen, P. (2015). Negligible respiratory irritation and inflammation potency of pigmentary TiO2 in mice. Inh. Toxicol.  27: 378-386, PMID: 26176585, DOI: 10.3109/08958378.2015.1056890