Read across for the derivation of Indoor Air Guidance Values supported by PBTK modelling

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Abstract

Polyurethane Flexible Foams (PUF) are versatile materials used in upholstered furniture and bed mattresses. Due to the production procedure, fresh foams emit volatile organic compounds (VOC) which may contribute to indoor air exposure. To evaluate the risk for consumers, the VOC concentration measured in chamber tests can be matched against existing benchmarks for indoor air like “Richtwerte” (RW) of the German UBA (Umweltbundesamt), “Lowest Concentration of Interest” (LCI) for construction products or derived no effect levels (DNEL) for consumer inhalation exposure. In a previous paper a method for the derivation of Indoor Air Guidance Values (IAGV) for VOC without RW, LCI or DNEL was developed. The method described made use of a sufficient toxicological database. For substances with an insufficient database, read across to structural analogues is a way forward to estimate Indoor Air Guidance Values (IAGV). In this work a read across exercise, supported by an open source physiology based toxicokinetic (PBTK) modelling program is demonstrated. The use of enzyme kinetic data for phase I and phase II metabolism is discussed and areas for further work were identified. For two substances with very limited toxicological data, allyloxypropanol (isomer mixture of 1-allyloxy-2-propanol and 2-allyloxy-1-propanol) and 2,3-di-ethyl-2,3-dimethylsuccinodintrile, Tentative Indoor Air Guidance Values of 750 µg/m³ and 65 µg/m³ were derived.

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Most cited references 22

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Hermann M. Bolt, Peter Roos, Ricarda Thier (2003)

The importance of the isoform CYP2E1 of the human cytochrome P-450 superfamily of enzymes for occupational and environmental medicine is derived from its unique substrate spectrum that includes a number of highly important high-production chemicals, such as aliphatic and aromatic hydrocarbons, solvents and industrial monomers (i.a. alkanes, alkenes, aromatic and halogenated hydrocarbons). Many polymorphic genes, such as CYP2E1, show considerable differences in allelic distribution between different human populations. The polymorphic nature of the human CYP2E1 gene is significant for inter-individual differences in toxicity of its substrates. Since the substrate spectrum of CYP2E1 includes many compounds of basic relevance to industrial toxicology, a rationale for metabolic interactions of different CYP2E1 substrates is provided. In-depth research into the inter-individual phenotypic differences of human CYP2E1 enzyme activities was enabled by the recognition that the 6-hydroxylation of the drug chlorzoxazone is mediated by CYP2E1. Studies on CYP2E1 phenotyping have pointed to inter-individual variations in enzyme activities. There are consistent ethnic differences in CYP2E1 enzyme expression, mostly demonstrated between European and Japanese populations, which point to a major impact of genetic factors. The most frequently studied genetic polymorphisms are the restriction fragment length polymorphisms PstI/ RsaI (mutant allele: CYP2E1*5B) located in the 5'-flanking region of the gene, as well as the DraI polymorphism (mutant allele: CYP2E1*6) located in intron 6. These polymorphisms are partly related, as they form the common allele designated CYP2E1*5A. Striking inter-ethnic differences between Europeans and Asians appear with respect to the frequencies of the CYP2E1*5A allele (only approximately 5% of Europeans are heterozygous, but 37% of Asians are, whilst 6% of Asians are homozygous). Available studies indicate a wide variation in human CYP2E1 expression, which are very likely based on complex gene-environment interactions. Major inter-ethnic differences are apparent on the genotyping and the phenotyping levels. Selected cases are presented where inter-ethnic variations of CYP2E1 may provide likely explanations for unexplained findings concerning industrial chemicals that are CYP2E1 substrates. Possible consequences of differential inter-individual and inter-ethnic susceptibilities are related to individual expressions of clinical symptoms of chemical toxicity, to results of biological monitoring of exposed workers, and to the interpretation of results of epidemiological or molecular-epidemiological studies.

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A compilation of two decades of mutagenicity test results with the Ames Salmonella typhimurium and L5178Y mouse lymphoma cell mutation assays.

H E Seifried, R Seifried, J. J. Clarke … (2006)

As previously reported [Cameron, T. P., Rogers-Back, A. M., Lawlor, T. E., Harbell, J. W., Seifried, H. E., and Dunkel, V. C. (1991) Gentoxicity of multifunctional acrylates in the Salmonella/mammalian-microsome assay and mouse lymphoma TK+/- assay. Environ. Mol. Mutagen. 17, 264-271], the National Cancer Institute (NCI) shares the responsibility of selecting the most significant chemicals for carcinogenicity testing by the National Toxicology Program (NTP) and has used data from Salmonella and mouse lymphoma mutagenicity assays to aid in the selection and prioritization of chemicals to be further evaluated in chronic 2 year rodent studies. In addition, a number of antineoplastic and anti-AIDS drugs in preclinical evaluation were tested for the NCI's Division of Cancer Treatment Toxicology Branch. In the NCI/NTP chemical selection process, it is no longer necessary to test chemicals prior to sending them to the NTP so the NCI program has ceased performing mutagenicity tests. Some of the testing data has been made available in summary form in the Chemical Carcinogenisis Research Information System (CCRIS), which is searchable on the NLM TOXNET system. The limitations in using this source are that only summary results are available and many negative test results are not included. A summary table that presents the results for each compound is provided in the Appendix with raw data provided in the Supporting Information. The Appendix table contains the compound name, CAS number, and a summary of the data from the Ames test and the mouse lymphoma assay.

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Author and article information

Journal

Journal ID (nlm-ta): EXCLI J

Journal ID (iso-abbrev): EXCLI J

Journal ID (publisher-id): EXCLI J

Title: EXCLI Journal

Publisher: Leibniz Research Centre for Working Environment and Human Factors

ISSN (Electronic): 1611-2156

Publication date (Electronic): 05 November 2018

Publication date Collection: 2018

Volume: 17

Pages: 1069-1078

Affiliations

[1 ]Muenster University of Applied Science, Chemical Engineering, Stegerwaldstrasse 39,D-48565 Steinfurt, GERMANY

Author notes

*To whom correspondence should be addressed: Thomas Schupp, Muenster University of Applied Science, Chemical Engineering, Stegerwaldstrasse 39,D-48565 Steinfurt, GERMANY; Tel.: +49 2551 962595, E-mail: thomas.schupp@ 123456fh-muenster.de

Article

Publisher ID: 2018-1734 Publisher ID: Doc1069

DOI: 10.17179/excli2018-1734

PMC ID: 6295638

PubMed ID: 30564084

SO-VID: 54dca4c2-dcb2-4337-a883-3494628c5cb8

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence ( http://creativecommons.org/licenses/by/4.0/) You are free to copy, distribute and transmit the work, provided the original author and source are credited.

History

Date received : 20 September 2018

Date accepted : 24 October 2018

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