Filters

96
Reset filters

Settings
Author: Mangelsdorf, I. ×

Publications Search Results

Now showing 1 - 10 of 96
  • Publication
    Risk assessment for irritating chemicals - Derivation of extrapolation factors
    ( 2021)
    Mangelsdorf, I.
    ;
    Schröder, K.
    ;
    Escher, S.E.
    ;
    Kolossa-Gehring, M.
    ;
    Debiak, M.
    Irritation of the eyes and the upper respiratory tract are important endpoints for setting guide values for chemicals. To optimize the use of the often-limited data, we analysed controlled human exposure studies (CHS) with 1-4 h inhalation of the test substance, repeated dose inhalation studies in rodents, and Alarie-Tests and derived extrapolation factors (EF) for exposure duration, inter- and intraspecies differences. For the endpoint irritating effects in the respiratory tract in rodents, geometric mean (GM) values of 1.9 were obtained for the EF for subacuteRTsubchronic (n = 16), 2.1 for subchronicRTchronic (n = 40), and 2.9 for subacuteRTchronic (n = 10) extrapolation. Based on these data we suggest an EF of 2 for subchronicRTchronic and of 4 for subacuteRTchronic extrapolation. In CHS, exposure concentration determines the effects rather than exposure duration. Slight reversible effects during 4 h exposure indicate that an EF of 1 can be considered for assessing chronic exposures. To assess species extrapolation, 10 chemicals were identified with both, reliable rat inhalation studies and CHS. The GM of the ratio between the No Observed Adverse Effect Concentration (NOAEC) in rats and humans was 2.3 and increased to 3.6 when expanding the dataset to all available EF (n = 25). Based on these analyses, an EF of 3 is suggested to extrapolate from a NOAEC in a chronic rat study to a NOAEC in a CHS. The analysis of EFs for the extrapolation from a 50% decrease in respiratory frequency in the Alarie test in mice (RD50) to a NOAEC in a CHS resulted in a GM of 40, for both, the reliable (n = 11) and the overall dataset (n = 19). We propose to use the RD50 from the Alarie test for setting guide values and to use 40 as EF. Efs for intraspecies differences in the human population must account for susceptible persons, most importantly for persons with chemical intolerance (CI), who show subjective signs of irritation at low concentrations. The limited data available do not justify to deviate from an EF of 10 - 20 as currently used in different regulatory settings.
  • Publication
    Time extrapolation in regulatory risk assessment: The impact of study differences on the extrapolation factors
    ( 2020)
    Escher, S.E.
    ;
    Mangelsdorf, I.
    ;
    Hoffmann-Doerr, S.
    ;
    Partosch, F.
    ;
    Karwath, A.
    ;
    Schroeder, K.
    ;
    Zapf, A.
    ;
    Batke, M.
    In human risk assessment, time extrapolation factors (EFs) account for differences in exposure duration of experimental studies. We calculated EFs based on N(L)OEL (no (lowest) observed effect level) ratios, dividing shorter-term by longer-term values. The 'oral' datasets comprised 302 EFs (subacute-subchronic) and 1059 EFs (subchronic-chronic). The 'inhalation' datasets contained 67 EFs (subacute-subchronic) and 226 EFs (subchronic-chronic). The experimental EF distribution oral:subchronic-chronic showed that study parameters like deviation in dose selection and spacing influence mainly the data variance. Exclusion of these influences led to a dataset representing more realistically the difference of N(L)OELs with prolonged treatment. This dataset showed a GM of 1.5, indicating that the impact of a longer treatment period on the study N(L)OEL is on average not high. A factor of 1.5 seemed to be also sufficiently conservative for subacute-subchronic and subchronic-chronic extrapolation (inhalation or oral exposure). EFs for groups of similar compounds did not differ, but for compounds with low and high NOEL values. Relatively toxic compounds (GM 1) might thus not require time extrapolation. Within and between chemical variance was analysed in the dataset oral:subchronic-chronic (GSD 4.8). The variance between chemicals should be considered within extrapolation by selecting an appropriate percentile for which a chemical variance factor is suggested. In risk assessment, often a combination of EFs is required. Our analysis indicates that such a combination will result in an accumulation of non-toxicological variance and therefore unrealistically high EFs. Further evaluations are needed to identify appropriate chemical variance factors for these situations.
  • Publication
    Data-mining in toxicology
    ( 2014)
    Mangelsdorf, I.
    Literature searches are necessary to find answers to many toxicological issues. Fortunately, today we are no longer reliant on time-consuming searches in reference books, but can make use of the Internet as an important tool for gathering information. A lot of information including complete substance assessments is easily available and free of charge. Because of the large variety of possible data sources, however, literature searches are nevertheless difficult to undertake and in addition can take a lot of time. Depending on the particular issue of research, different searching strategies should be used.
  • Publication
    Interspecies extrapolation based on the RepDose database
    ( 2013)
    Escher, S.E.
    ;
    Batke, M.
    ;
    Hoffmann-Doerr, S.
    ;
    Messinger, H.
    ;
    Mangelsdorf, I.
    Repeated dose toxicity studies from the RepDose database (DB) were used to determine interspecies differences for rats and mice. NOEL (no observed effect level) ratios based on systemic effects were investigated for three different types of exposure: inhalation, oral food/drinking water and oral gavage. Furthermore, NOEL ratios for local effects in inhalation studies were evaluated. On the basis of the NOEL ratio distributions, interspecies assessment factors (AF) are evaluated. All data sets were best described by a lognormal distribution. No difference was seen between inhalation and oral exposure for systemic effects. Rats and mice were on average equally sensitive at equipotent doses with geometric mean (GM) values of 1 and geometric standard deviation (GSD) values ranging from 2.30 to 3.08. The local AF based on inhalation exposure resulted in a similar distribution with GM values of 1 and GSD values between 2.53 and 2.70. Our analysis confirms former analyses on interspecies differences, including also dog and human data. Furthermore it supports the principle of allometric scaling according to caloric demand in the case that body doses are applied. In conclusion, an interspecies distribution animal/human with a GM equal to allometric scaling and a GSD of 2.5 was derived.
  • Publication
  • Publication
    Change in agglomeration status and toxicokinetic fate of various nanoparticles in vivo following lung exposure in rats
    ( 2012)
    Creutzenberg, O.
    ;
    Bellmann, B.
    ;
    Korolewitz, R.
    ;
    Koch, W.
    ;
    Mangelsdorf, I.
    ;
    Tillmann, T.
    ;
    Schaudien, D.
    The deposition characteristics in lungs following inhalation, the potential toxic effects induced and the toxicokinetic fate including a possible translocation to other sites of the body are predominantly determined by the agglomeration status of nanoscaled primary particles. Systemic particle effects, i.e. effects on remote organs besides the respiratory tract are considered to be of relevant impact only for de-agglomerated particles with a nanoscaled aspect. Rats were exposed to various types of nanoscaled particles, i.e. titanium dioxide, carbon black and constantan. These were dispersed in physiologically compatible media, e. g. phosphate buffer, sometimes including auxiliaries. Rats were treated with aqueous nanoparticle dispersions by intratracheal instillation or were exposed to well-characterized nanoparticle aerosols. Subsequently, alterations in the particle size distribution were studied using transmission electron microscopy (TEM) as well as the bronchoalveolar lavage (BAL) technique. Based on the results in various approaches, a tendency of nanoscaled particles to form larger size agglomerates following deposition and interaction with cells or the respiratory tract is predominant. The contrary trend, i.e. the increase of particle number due to a disintegration of agglomerates seems not to be of high relevance.
  • Publication
    Toxicological properties and risk assessment of the anionic surfactants category: Alkyl sulfates, primary alkane sulfonates, and alpha-olefin sulfonates
    ( 2011)
    Wibbertmann, A.
    ;
    Mangelsdorf, I.
    ;
    Gamon, K.
    ;
    Sedlak, R.
    The category of the anionic surfactants (ANS) consisting of 46 alkyl sulfates, 6 primary alkane sulfonates, and 9 @-olefin sulfonates has been assessed under the high production volume (HPV) chemicals program of the Organisation for Economic Cooperation and Development (OECD) in 2007. In this review the toxicological properties of these chemicals are summarized. The chemicals of this category are used predominantly in detergents, household cleaning products, and cosmetics. These chemicals show low acute and repeat dose toxicity. There was no evidence of genetic or reproductive toxicity, or carcinogenicity. There also was no indication for sensitizing properties. Skin and eye irritating effects in consumers are not to be expected. For consumers, the calculated body burden is about 10,000 times lower than the lowest NOAEL value in experimental animals, so that adverse effects caused by substances of the ANS category can be excluded.
  • Publication
    Evaluation of time extrapolation factors based on the database RepDose
    ( 2011)
    Batke, M.
    ;
    Escher, S.
    ;
    Hoffmann-Doerr, S.
    ;
    Melber, C.
    ;
    Messinger, H.
    ;
    Mangelsdorf, I.
    In chemical risk assessment for many substances only short-term animal studies are available for the evaluation of long-term human exposure. Therefore usually extrapolation factors (EF) are used to extrapolate NOAELs from existing short-term studies to NOAELs for long term exposure. In this report time EFs are derived, based on NOEL/C or LOEL/C ratios (short term N(L)OEL/long term N(L)OEL) from the large datasets of the database RepDose (www.fraunhofer-repdose.de) on repeated dose toxicity for oral or inhalation administration. Within a tiered approach several sources of variability, e.g. use of LOEL/C ratios or differences in dose spacing were analyzed and if needed subsequently excluded. The reduction of data variability resulted in "final" EFs datasets, which are as far as possible based on compound-specific, time-dependent differences in toxicity. For distribution functions of oral repeated dose toxicity studies characterised by GM, GSD and 90th percentiles the following data are obtained: subacute-to-subchronic - GM 1.3, GSD 2.4, 90th 4.0, subacute-to-chronic - GM 3.4, GSD 3.7, 90th 18.2, and subchronic-to-chronic - GM 1.4, GSD 2.1, 90th 3.6. The number of data for inhalation exposure is limited, but with regard to systemic toxicity the derived EFs confirm the respective oral EFs.
  • Publication
    Improvement of the Cramer classification for oral exposure using the database TTC RepDose - A strategy description
    ( 2011)
    Tluczkiewicz, I.
    ;
    Buist, H.E.
    ;
    Martin, M.T.
    ;
    Mangelsdorf, I.
    ;
    Escher, S.E.
    The present report describes a strategy to refine the current Cramer classification of the TTC concept using a broad database (DB) termed TTC RepDose. Cramer classes 1-3 overlap to some extent, indicating a need for a better separation of structural classes likely to be toxic, moderately toxic or of low toxicity.Groups of structurally similar compounds of high toxicity in Cramer class 1 and of moderate to low toxicity in Cramer class 3 were identified and reassigned to the appropriate Cramer class according to their observed toxicological potency in in vivo studies. This refinement results in a better discrimination of Cramer classes 1 and 3 and an increased number of substances in Cramer class 2. The TTC values are 8.7 mol/person/d (class 1), 6.72 mol/person/d (class 2) and 0.28mol/person/d (class 3). Assuming a median molecular weight of 220. g/mol for the compounds of the TTC RepDose DB, the corresponding TTC values are 1930, 1478 and 63 g/person/d for classes 1, 2 a nd 3 respectively. The derived thresholds are close to the TTC values initially proposed by Munro with 1800, 540 and 90 g/person/d for classes 1, 2 and 3 respectively. Additional structural classes are discussed with a view to further refinement of the current Cramer classification scheme.