Restricted accessResearch articleFirst published online 2022-9
Evaluation of animal toxicity studies with diisocyanates regarding presence of thresholds for induction and elicitation of respiratory allergy by quantitative weight of evidence
Animal toxicity studies on diisocyanates were evaluated using quantitative weight of evidence (QWoE) to test the hypothesis that the dose-response curve shows a threshold for the induction and/or elicitation of respiratory sensitization. A literature search identified 59 references that included at least two concentration groups of the diisocyanate and a vehicle-exposed concurrent control in the study design. These studies were subjected to a QWoE-assessment applying scoring criteria for quality and relevance/strength of effects relevant to the selected endpoint of respiratory sensitization. Overall, the studies assessing dose/concentration-response for diisocyanates with the endpoint, respiratory sensitization, were heterogenous regarding study design, animal models used, endpoints assessed, and quality. Only a limited number of the studies subjected to the QWoE-assessment allowed drawing conclusions about possible thresholds for respiratory sensitization. Highest quality and relevance/strength of effects scores were obtained by a series of studies specifically designed to investigate a potential threshold for elicitation of respiratory sensitization in the Brown Norway (BN) rat. These studies applied an elaborate study design to optimize induction of respiratory sensitization and reduce interference by respiratory tract irritation. In summary, the available studies provided moderate to good support for the existence of a threshold for elicitation and limited to moderate support for a threshold regarding induction of respiratory allergy by diisocyanates in experimental animals. However, a quantitative extrapolation of threshold values established in rodents to humans remains complex.
American Conference of Governmental Industrial Hygienists (ACGIH) (1986) Methylene Bisphenyl Isocyanate. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH, USA: ACGIH.
2.
American Conference of Governmental Industrial Hygienists (ACGIH) (2016) Toluene Diisocyanate, 2.4- or 2.6- (Or as a Mixture) [newly Adopted TLV Documentation]. Cincinnati, OH, USA: ACGIH
3.
Agence nationale de sécurité sanitaire de l'alimentation de l'environnement et du travail (ANSES) (2019) French Agency for Food Environmental and Occupational Health & SafetyExpert Appraisal on Recommending Occupational Exposure Limits for Chemical Agents, Assessment of Health Effects and Methods for the Measurement of Exposure Levels in Workplace Atmospheres for Toluene Diisocyanate Mixed Isomers (TDI) CAS No. 26471-62.-5 (draft for public consultation). Paris, F: ANSES
4.
AoyamaKHuangJUedaA, et al. (1994) Provocation of respiratory allergy in guinea pigs following inhalation of free toluene diisocyanate. Archives of Environmental Contamination and Toxicology26: 403–407.
5.
ArtsJ (2020) How to assess respiratory sensitization of low molecular weight chemicals?International Journal of Hygiene and Environmental Health225: 113469.
6.
ArtsJHde JongWHvan TrielJJ, et al. (2008) The respiratory local lymph node assay as a tool to study respiratory sensitizers. Toxicological Sciences106(2): 423–434.
7.
ArtsJHKuperCF (2007) Animal models to test respiratory allergy of low molecular weight chemicals: a guidance. Methods41(1): 61–71.
8.
ArtsJHKuperCF (2003) Approaches to induce and elicit respiratory allergy: impact of route and intensity of exposure. Toxicology Letters140-141: 213–222.
9.
ArtsJHMommersCde HeerC (2006) Dose-response relationships and threshold levels in skin and respiratory allergy. Critical Reviews in Toxicology36(3): 219–251.
10.
ArtsJHEBloksmaNKuperCF (2004a) Respiratory allergy in the rat: impact of route and intensity of exposure during sensitisation (Abstract). Toxicology and Applied Pharmacology197: 175.
11.
ArtsJHEde KoningMWBloksmaN, et al. (2004b) Respiratory allergy to trimellitic anhydride in rats: concentration-response relationships during elicitation. Inhalation Toxicology16(5): 259–269.
12.
ATSDR (2018) Agency for Toxic Substances and Disease Registry (ATSDR), Toxicological Profile for Toluene Diisocyanate and Methylenediphenyl Diisocyanate. Atlanta, GA: US Department of Health and Human Services, Public Health Service.
13.
AunMVBonamichi-SantosRArantes-CostaFM, et al. (2017) Animal models of asthma: utility and limitations. Journal of Asthma and Allergy10: 293–301.
14.
BanMHettichDGoutetM, et al. (1997) TDI inhalation in guinea-pigs involves migration of dendritic cells. Toxicology Letters93: 185–194.
15.
BeroniusAMolanderLZilliacusJ, et al. (2018) Testing and refining the Science in Risk Assessment and Policy (SciRAP) web-based platform for evaluating the reliability and relevance of in vivo toxicity studies. Journal of Applied Toxicology38(12): 1460–1470.
16.
BlaikieLMorrowTWilsonAP, et al. (1995) A two-centre study for the evaluation and validation of an animal model for the assessment of the potential of small molecular weight chemicals to cause respiratory allergy. Toxicology96(1): 37–50.
17.
BothamPAHextPMRattrayNJ, et al. (1988) Sensitisation of guinea pigs by inhalation exposure to low molecular weight chemicals. Toxicology Letters41(2): 159–173.
18.
BridgesJSolomonKR (2016) Quantitative weight-of-evidence analysis of the persistence, bioaccumulation, toxicity, and potential for long-range transport of the cyclic volatile methyl siloxanes. Journal of Toxicology and Environmental Health Part B: Critical Reviews19(8): 345–379.
19.
California-EPA (2014) California environmental protection agency, toluene diisocyanate reference exposure levels: technical support document for the derivation of noncancer reference exposure levels, appendix D1. OEHHA Air Toxicology and Epidemiology Hot Spots Program. [Proposed revision]. Sacramento, CA, USA: California Environmental Protection Agency.
20.
CanningBJChouY (2008) Using guinea pigs in studies relevant to asthma and COPD. Pulmonary Pharmacology & Therapeutics21(5): 702–720.
21.
CharyAHennenJKleinSG, et al. (2018) Respiratory sensitization: toxicological point of view on the available assays. Archives of Toxicology92(2): 803–822.
22.
CochraneSAArtsJHEEhnesC, et al. (2015) Thresholds in chemical respiratory sensitisation. Toxicology333: 179–194.
23.
De JongWHArtsJHDe KlerkA, et al. (2009) Contact and respiratory sensitizers can be identified by cytokine profiles following inhalation exposure. Toxicology261(3): 103–111.
24.
De VooghtVVanoirbeekJALuytsK, et al. (2010) Choice of mouse strain influences the outcome in a mouse model of chemical-induced asthma. Plos One5(9): e12581.
25.
DearmanRKimberI (2005) Respiratory allergy to chemicals: hazard identification and characterisation. Toxicology213(3): 215–216.
26.
DekantW (2019) Tetrahydrofuran-induced tumors in rodents are not relevant to humans: quantitative weight of evidence analysis of mode of action information does not support classification of tetrahydrofuran as a possible human carcinogen. Regulatory Toxicology and Pharmacology109: 104499.
27.
DekantWBridgesJ (2016a) Assessment of reproductive and developmental effects of DINP, DnHP and DCHP using quantitative weight of evidence. Regulatory Toxicology and Pharmacology81: 397–406.
28.
DekantWBridgesJ (2016b) A quantitative weight of evidence methodology for the assessment of reproductive and developmental toxicity and its application for classification and labeling of chemicals. Regulatory Toxicology and Pharmacology82: 173–185.
29.
DekantWBridgesJScialliAR (2017) A quantitative weight of evidence assessment of confidence in modes-of-action and their human relevance. Regulatory Toxicology and Pharmacology90: 51–71.
30.
European Chemicals Agency (ECHA) (2019) Scientific Report for Evaluation of Limit Values for Diisocyanates at the Workplace. Helsinki, FI: ECHA.
31.
European Chemical Agency, Committee for Risk Assessment (ECHA-RAC) (2021) CLH report for 3,3'-dimethylbiphenyl-4,4'-diyl diisocyanate EC No 202-112-7, CAS No 91-97-4 prepared by Agence nationale de sécurité sanitaire de l'alimentation de l'environnement et du travail (ANSES) and Federal Institute for Occupational Safety and Health (BAuA). Helsinki, FI: ECHA.Annex 1. Background document to the Opinion proposing harmonised classification and labelling at EU level of 3,3'-dimethylbiphenyl-4,4'-diyl diisocyanate EC No 202-112-7, CAS No 91-97-4
32.
GagnaireFBanMMicillinoJC, et al. (1996) Bronchial responsiveness and inflammation in guinea-pigs exposed to toluene diisocyanate: a study on single and repeated exposure. Toxicology114(2): 91–100.
33.
GagnaireFMicillinoJCBonnetP, et al. (1988) Toluene diisocyanate-induced airway hyperresponsiveness to intravenous acetylcholine: a study on single and repeated exposure in guinea-pigs. Toxicology Letters44: 273–280.
34.
GloedeECichockiJABaldinoJB, et al. (2011) A validated hybrid computational fluid dynamics-physiologically based pharmacokinetic model for respiratory tract vapor absorption in the human and rat and its application to inhalation dosimetry of diacetyl. Toxicological Sciences123(1): 231–246.
35.
HesbertABanMBonnetP, et al. (1991) Interdependence of polymorphonuclear neutrophils and macrophages stained for N-acetyl-beta-glucosaminidase in lavage effluents from toluene diisocyanate-exposed rat lungs. Toxicology Letters56(1–2): 53–59.
36.
HolsappleMPJonesDKawabataTT, et al. (2006) Assessing the potential to induce respiratory hypersensitivity. Toxicological Sciences91(1): 4–13.
37.
HuangJAoyamaKUedaA (1993a) Experimental study on respiratory sensitivity to inhaled toluene diisocyanate. Archives of Toxicology67(6): 373–378.
38.
HuangJWangXPChenBM, et al. (1993b) Dose-response relationships for chemical sensitization from TDI and DNCB. Bulletin of Environmental Contamination and Toxicology51(5): 732–739.
39.
KarolMH (1983) Concentration-dependent immunologic response to toluene diisocyanate (TDI) following inhalation exposure. Toxicology and Applied Pharmacology68: 229–241.
40.
KarolMH (1994) Animal models of occupational asthma. European Respiratory Journal7(3): 555–568.
41.
KimberIDearmanRJBasketterDA, et al. (2014) Chemical respiratory allergy: reverse engineering an adverse outcome pathway. Toxicology318: 32–39.
42.
KimberIPooleABasketterDA (2018) Skin and respiratory chemical allergy: confluence and divergence in a hybrid adverse outcome pathway. Toxicol Res (Camb)7(4): 586–605.
43.
KlimischHJAndreaeMTillmannU (1997) A systematic approach for evaluating the quality of experimental toxicological and ecotoxicological data. Regulatory Toxicology and Pharmacology25(1): 1–5.
44.
KouadioKZhengKCToureAA, et al. (2014) IL-4 and IL-5 secretions predominate in the airways of wistar rats exposed to toluene diisocyanate vapor. Journal of Preventive Medicine and Public Health47(1): 57–63.
45.
KouadioKZhengKCTuekpeMK, et al. (2005) Airway inflammatory and immunological events in a rat model exposed to toluene diisocyanate. Food and Chemical Toxicology43(8): 1281–1288.
46.
MarekWPotthastJMarczynskiB, et al. (1995) Toluene diisocyanate induction of airway hyperresponsiveness at the threshold limit value (10 ppb) in rabbits. Lung173: 333–346.
47.
MarekWPotthastJMarczynskiB, et al. (1999) Subchronic exposure to diisocyanates increases guinea pig tracheal smooth muscle responses to acetylcholine. Respiration66(2): 156–161.
48.
MathesonJMJohnsonVJVallyathanV, et al. (2005) Exposure and immunological determinants in a murine model for toluene diisocyanate (TDI) asthma. Toxicological Sciences84: 88–98.
49.
MekenyanOPatlewiczGKusevaC, et al. (2014) A mechanistic approach to modeling respiratory sensitization. Chemical Research in Toxicology27(2): 219–239.
50.
MullinLSWoodCKKrivanekND (1983) Guinea pig respiratory response to isocyanates. Toxicology and Applied Pharmacology71(1): 113–122.
51.
NorthCMEzendamJHotchkissJA, et al. (2016) Developing a framework for assessing chemical respiratory sensitization: a workshop report. Regulatory Toxicology and Pharmacology80: 295–309.
52.
PauluhnJ (1997) Assessment of respiratory hypersensitivity in guinea pigs sensitized to toluene diisocyanate: improvements on analysis of respiratory response. Fundamental and Applied Toxicology40: 211–219.
53.
PauluhnJ (2005) Brown Norway rat asthma model of diphenylmethane 4,4'-diisocyanate. Inhalation Toxicology17: 729–739.
54.
PauluhnJ (2008a) Brown Norway rat asthma model of diphenylmethane-4,4'-diisocyanate (MDI): analysis of the elicitation dose-response relationship. Toxicological Sciences104(2): 320–331.
55.
PauluhnJ (2008b) Brown Norway rat asthma model of diphenylmethane-4,4'-diisocyanate (MDI): impact of vehicle for topical induction. Regulatory Toxicology and Pharmacology50(1): 144–154.
56.
PauluhnJ (2014) Development of a respiratory sensitization/elicitation protocol of toluene diisocyanate (TDI) in Brown Norway rats to derive an elicitation-based occupational exposure level. Toxicology319: 10–22.
57.
PauluhnJ (2015) Analysis of the interrelationship of the pulmonary irritation and elicitation thresholds in rats sensitized with 1,6-hexamethylene diisocyanate (HDI). Inhalation Toxicology27(4): 191–206.
58.
PauluhnJ (2019) Concentration x time analyses of sensory irritants revisited: weight of evidence or the toxic load approach. that is the question. Toxicology Letters316: 94–108.
59.
PauluhnJEbenA (1991) Validation of a non-invasive technique to assess immediate or delayed onset of airway hypersensitivity in guinea-pigs. Journal of Applied Toxicology11(6): 423–431.
60.
PauluhnJEidmannPMohrU (2002) Respiratory hypersensitivity in guinea pigs sensitized to 1,6-hexamethylene diisocyanate (HDI): comparison of results obtained with the monomer and homopolymers of HDI. Toxicology171(2–3): 147–160.
61.
PauluhnJEmuraMMohrU, et al. (1999) Two-week inhalation toxicity of polymeric diphenylmethane-4,4'-diisocyanate (PMDI) in rats: analysis of biochemical and morphological markers of early pulmonary response. Inhalation Toxicology11: 1143–1163.
62.
PauluhnJMohrU (1994) Assessment of respiratory hypersensitivity in guinea-pigs sensitized to diphenylmethane-4,4'-diisocyanate (MDI) and challenged with MDI, acetylcholine or MDI-albumin conjugate. Toxicology92: 53–74.
63.
PauluhnJMohrU (1998) Assessment of respiratory hypersensitivity in guinea pigs sensitized to toluene diisocyanate: a comparison of sensitization protocols. Inhalation Toxicology10: 131–154.
64.
PauluhnJMohrU (2001) Inhalation toxicity of 1,6-hexamethylene diisocyanate homopolymers (HDI-IC and HDI-BT): results of subacute and subchronic repeated inhalation exposure studies. Inhalation Toxicology13(6): 513–532.
65.
PauluhnJMohrU (2005) Experimental approaches to evaluate respiratory allergy in animal models. Experimental and Toxicologic Pathology56(4–5): 203–234.
66.
PauluhnJPooleA (2011) Brown Norway rat asthma model of diphenylmethane-4,4'-diisocyanate (MDI): determination of the elicitation threshold concentration of after inhalation sensitization. Toxicology281(1–3): 15–24.
67.
PauluhnJRungelerWMohrU (1995) Phenyl isocyanate-induced asthma in rats following a 2-week exposure period. Fundamental and Applied Toxicology24(2): 217–228.
68.
PauluhnJThielAEmuraM, et al. (2000) Respiratory sensitization to diphenyl-methane-4,4'-diisocyanate (MDI) in guinea pigs: impact of particle size on induction and elicitation of response. Toxicological Sciences56(1): 105–113.
69.
PonsFHaagMCorcosL, et al. (2000) Inhalation of toluene diisocyanate affects cytochrome P450 2B1 expression in rat lung. Archives of Toxicology74(7): 397–403.
RaulfMTennieLMarczynskiB, et al. (1995) Cellular and mediator profile in bronchoalveolar lavage of guinea pigs after toluene diisocyanate (TDI) exposure. Lung173(1): 57–68.
72.
RhombergLRGoodmanJEBaileyLA, et al. (2013a) A survey of frameworks for best practices in weight-of-evidence analyses. Critical Reviews in Toxicology43(9): 753–784.
73.
RhombergLRGoodmanJEPrueittRL (2013b) The weight of evidence does not support the listing of styrene as "reasonably anticipated to be a human carcinogen" in ntp's twelfth report on carcinogens. Human and Ecological Risk Assessment19(1): 4–27.
74.
SanghaGKAlarieY (1979) Sensory irritation by toluene diisocyanate in single and repeated exposures. Toxicology and Applied Pharmacology50: 533–547.
75.
SanghaGKMatijakMAlarieY (1981) Comparison of some mono- and diisocyanates as sensory irritants. Toxicology and Applied Pharmacology57: 241–246.
76.
SchroeterJDKimbellJSAsgharianB, et al. (2013) Inhalation dosimetry of hexamethylene diisocyanate vapor in the rat and human respiratory tracts. Inhalation Toxicology25(3): 168–177.
77.
SchuppTCollinsMA (2012) Toluene diisocyanate (TDI) airway effects and dose-responses in different animal models. EXCLI Journal11: 416–435.
78.
ShiotsukaRNWarrenDLHalliburtonAT, et al. (2000) A comparative respiratory sensitization study of 2,4- and 2,6-toluene diisocyanate using guinea pigs. Inhalation Toxicology12: 605–615.
79.
StadlerJKarolMH (1984) Experimental delayed hypersensitivity following inhalation of dicyclohexylmethane-4,4'-diisocyanate: a concentration-response relationship. Toxicology and Applied Pharmacology74: 244–249.
80.
SullivanKMEnochSJEzendamJ, et al. (2017) An adverse outcome pathway for sensitization of the respiratory tract by low-molecular-weight chemicals: building evidence to support the utility of in vitro and in silico methods in a regulatory context. Applied In Vitro Toxicology3(3): 213–226.
81.
ValentiniJEWongKLAlarieY (1983) Single-tracer technique to evaluate pulmonary edema and its application to detect the effect of hexamethylene diisocyanate trimer aerosol exposures. Toxicology and Applied Pharmacology69: 461–470.
82.
Van Der KraakGJHosmerAJHansonML, et al. (2014) Effects of atrazine in fish, amphibians, and reptiles:aAn analysisbBased on quantitative weight of evidence. Critical Reviews in Toxicology44(sup5): 1–66.
83.
WeyelDARodneyBSAlarieY (1982) Sensory irritation, pulmonary irritation, and acute lethality of a polymeric isocyanate and sensory irritation of 2,6-toluene diisocyanate. Toxicology and Applied Pharmacology64: 423–430.
84.
WeyelDASchafferRB (1985) Pulmonary and sensory irritation of diphenylmethane-4,4’- and dicyclohexylmethane-4,4’-diisocyanate. Toxicology and Applied Pharmacology77: 427–433.
85.
WongKLKarolMHAlarieY (1985) Use of repeated CO2 challenges to evaluate the pulmonary performance of guinea pigs exposed to toluene diisocyanate. Journal of Toxicology and Environmental Health15(1): 137–148.
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