1st International ESTP Expert Workshop: “Larynx squamous metaplasia”. A re-consideration of morphology and diagnostic approaches in rodent studies and its relevance for human risk assessment

Kaufmann, Wolfgang; Bader, Rainer; Ernst, Heinrich; Harada, Takanori; Hardisty, Jerry F.; Kittel, Birgit; Kolling, Angelika; Pino, Michael V.; Renne, Roger A.; Rittinghausen, Susanne; Schulte, Agnes; Wöhrmann, T.; Martin, Rachel W.

doi:10.1016/j.etp.2009.01.001

Cited by 53 publications

(48 citation statements)

References 27 publications

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“…Examples of such changes may include renal tubular dilatation, laryngeal metaplasia, hepatocellular lipidosis, biliary hyperplasia, and immune cell infiltrates (e.g., Kaufmann et al 2009;Hailey et al 2014). In some cases, dose-related increases in severity may be observed without dose-related increases in incidence due to the high-background incidence, complicating interpretation.…”

Section: Lesion Severitymentioning

confidence: 99%

“…A second example relates to laryngeal effects. According to Kaufmann et al (2009), minimal to mild focal laryngeal metaplasia in the absence of other related findings likely does not impair laryngeal or respiratory function and thus should not be considered adverse. However, when accompanied by inflammation, hyperkeratinization, necrosis, and/or hyperplasia, this constellation of effects may be considered adverse.…”

Section: Effect Constellationsmentioning

confidence: 99%

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Characterizing “Adversity” of Pathology Findings in Nonclinical Toxicity Studies

et al. 2016

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The identification of adverse health effects has a central role in the development and risk/safety assessment of chemical entities and pharmaceuticals. There is currently a need for better alignment regarding how nonclinical adversity is determined and characterized. The European Society of Toxicologic Pathology (ESTP) therefore coordinated a workshop to review available definitions of adversity, weigh determining and qualifying factors of adversity based on case examples, and recommend a practical approach to define and characterize adversity in toxicology reports, to serve as a valuable prerequisite for future organ-or lesion-specific workshops planned by the ESTP.

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Section: Lesion Severitymentioning

confidence: 99%

Section: Effect Constellationsmentioning

confidence: 99%

Characterizing “Adversity” of Pathology Findings in Nonclinical Toxicity Studies

et al. 2016

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“…Bei letzterem nimmt auch der Stärkegrad 1 bis 2 der plattenepithelartigen Metaplasien am Larynx mit zunehmender Expositionszeit nicht zu. Minimale bis leichte Plattenepithelzellmetaplasien, wie sie auch in den Inhalationsstudien mit Glycerin auftreten, sind als nicht advers zu bewerten (Kaufmann et al 2009 …”

Section: Mak-wert Es Liegen Keine Untersuchungen Beim Menschen Vor unclassified

“…Da die beobachteten Plattenepithelzellmetaplasien vom Schweregrad minimal bis leicht waren, sind sie als nicht advers zu bewerten (Kaufmann et al 2009 …”

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Glycerin [MAK Value Documentation in German language, 2016]

Laube¹,

Bartsch²,

Schriever‐Schwemmer³

et al. 2016

The MAK‐Collection for Occupational Health and Safety

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MAK Value Documentation for Glycerol The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated the maximum concentration at the work place (MAK value) of glycerol, considering the endpoints irritation of the respiratory tract and developmental toxicity. Since 2014, the Commission uses an empirical approach to set MAK values for substances with critical effects on the upper respiratory tract or the eyes. However, examination of the study results showed that this approach does not apply for glycerol, because glycerol is not an eye irritant and the minimal to slight metaplasia of the squamous epithelium of the larynx seen in rats at 662 mg/m 3 with glycerol aerosol is not interpreted as adverse. The response does not increase with the exposure duration. Therefore, the MAK value is raised to 200 mg glycerol/m 3 for the inhalable fraction. Peak Limitation Category I for local effects with an excursion factor of 2 is retained, as the effect is hardly concentration‐dependent, a sensory irritation is not known, and glycerol is, if at all, only slightly irritating to the eye. After scaling the oral NOAELs for developmental toxicity of 1310, 1280 and 1180 mg/kg bw and day for rats, mice, and rabbits, respectively, to a concentration at the work place (2293, 1280, and 3442 mg/m 3 ), the differences to the MAK value are considered so large, that damage to the embryo or foetus is unlikely when the MAK value is observed. The classification in Pregnancy Risk Group C is therefore retained.

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“…Minimal inflammation at the base of the epiglottis was detected in 1 female exposed to 10 mg/m 3 (REACH Ethanolamines Consortium SE 2010). This finding is not regarded as adverse because it occurs also as an incidental finding (Kaufmann et al 2009). …”

Section: Inhalationmentioning

confidence: 99%

2‐Aminoethanol [MAK Value Documentation, 2016]

Hartwig

Arand²

2018

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated the maximum concentration at the work place (MAK value) of 2‐aminoethanol [141‐43‐5], considering the endpoints respiratory tract irritation, developmental toxicity, and skin absorption. Available unpublished study reports are described in detail. Critical effect of 2‐aminoethanol is the local respiratory tract irritation. New 5‐day and 28‐day‐guideline‐studies with rats show time‐ and dose‐dependent effects in larynx (squamous metaplasia, inflammation, necrosis), trachea (squamous metaplasia, inflammation), and lung (hyperplasia of mucous and goblet cells). The NOAEC is 10 mg/m 3 (3,95 ml/m 3 ). Since 2014, the Commission uses an empirical approach to set MAK values for substances with critical effects on the upper respiratory tract or the eyes. Based on this approach, a concentration of 0.22 ml/m 3 for the work place air can be calculated from this study, resulting in a MAK value of 0.2 ml/m 3 . Since the critical effect is irritation, Peak Limitation Category I is retained with an excursion factor of 1 as the substance is corrosive. After scaling the oral NOAEL for developmental toxicity of 75, 225, and 500 mg/kg body weight and day for rabbits (dermal) and rats (dermal, oral), respectively, to an inhalation concentration at the work place, the differences to the MAK value, are considered sufficient, and damage to the embryo or foetus is unlikely when the MAK value is observed. Therefore, classification in Pregnancy Risk Group C is confirmed. Absorption via skin does not contribute significantly to the systemic toxicity of 2‐aminoethanol. Completed: March 23, 2015

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1st International ESTP Expert Workshop: “Larynx squamous metaplasia”. A re-consideration of morphology and diagnostic approaches in rodent studies and its relevance for human risk assessment

Cited by 53 publications

References 27 publications

Characterizing “Adversity” of Pathology Findings in Nonclinical Toxicity Studies

Characterizing “Adversity” of Pathology Findings in Nonclinical Toxicity Studies

Glycerin [MAK Value Documentation in German language, 2016]

2‐Aminoethanol [MAK Value Documentation, 2016]

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