Classification or non-classification of substances with positive tumor findings in animal studies: Guidance by the German MAK commission

One of the important tasks of the German Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (known as the MAK Commission) is in the evaluation of a potential for carcinogenicity of hazardous substances at the workplace. Often, this evaluation is critically based on data on carcinogenic responses seen in animal studies and, if positive tumor responses have been observed, this will mostly lead to a classification of the substance under investigation into one of the classes for carcinogens. However, there are cases where it can be demonstrated with a very high degree of confidence that the tumor findings in the experimental animals are not relevant for humans at the workplace and, therefore, the MAK Commission will not classify the respective substance into one of the classes for carcinogens. This paper will summarize the general criteria used by the MAK Commission for the categorization into “carcinogen” and “non-carcinogen” and compare this procedure with those used by other national and international organizations

Jo1-antisynthetase syndrome and severe interstitial lung disease with organising pneumonia on histopathology with favourable outcome on early combined treatment with corticosteroids, mycophenolate mofetil and rituximab

Antisynthetase syndrome is a rare autoimmune disease and represents a distinct entity within the idiopathic inflammatory myopathies. Its variable systemic manifestations are composed of myositis, interstitial lung disease, non-erosive arthritis, fever, Raynaud's phenomenon, hyperkeratotic skin changes and the presence of antibodies against aminoacyl-transfer-RNA-synthetases. Interstitial lung disease is the major determinant of morbidity and mortality. The role of lung biopsy remains controversial but it might be considered on an individual basis and may provide information regarding prognosis and treatment response. An integrated clinical, radiological and pathological approach to interstitial lung disease has to be emphasised. Due to the rarity of the disease, no standardised treatment guidelines for antisynthetase syndrome exist. We discuss a patient with anti-Jo1-autoantibody antisynthetase syndrome with proximal myositis and severe, rapid onset, interstitial lung disease with a histopathological pattern of organising pneumonia on surgical lung biopsy and good response to early combined immunosuppressive treatment with corticosteroids, mycophenolate mofetil and rituximab

TemBi 2014 mesocosm study: Summer storm impact on primary production rates and enzyme activities in Lake Stechlin

We simulated an experimental summer storm in large-volume (~1200 m3, ~16m depth) enclosures in Lake Stechlin (https://www.lake-lab.de) by mixing deeper water masses from the meta- and hypolimnion into the mixed layer (epilimnion). The mixing included the disturbance of a deep chlorophyll maximum (DCM) which was present at the same time of the experiment in Lake Stechlin and situated in the metalimnion of each enclosure during filling. Primary production rates as well as exoenzyme activities (alkaline phosphatase, beta-glucosidase, leucine aminopeptidase) were monitored for 42 days after the experimental disturbance event by incubation of size-fractionated sample with H14CO3- and MUF substrate analogue assays, respectively. Mixing disrupted the thermal stratification, increased concentrations of dissolved nutrients and CO2 and changed light conditions in the epilimnion. Thus, mixing stimulated phytoplankton production, resulting in higher primary production rates within one week after mixing

Troms� Center: Direction in a Complex Arctic System

For PA 860: Public Affairs Workshop, International IssuesThe authors examine the systemic nature of the issues affecting the Barents Euro-Arctic Region. The report focuses on five issues environmental concerns, indigenous groups, fisheries, oil and gas extraction, and maritime transport. The authors then provide proposals for projects that the center could focus on as well as recommendations for the structure of the center to help it address these issues

2‐Aminoethanol : MAK Value Documentation in German language, 2016

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, 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/m3 (3,95 ml/m3). 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/m3 for the work place air can be calculated from this study, resulting in a MAK value of 0.2 ml/m3. 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

4‐Methyl‐3‐penten‐2‐on : MAK Value Documentation in German language, 2016

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) for 4‐methyl‐3‐pentene‐2‐one of 5 ml/m3, considering local and systemic toxicity as well as developmental toxicity. As described in the last evaluation from 2006, 4‐methyl‐3‐pentene‐2‐one is irritating to eyes and skin. Starting at the lowest concentration of 31 ml/m3 in a 49‐day‐inhalation‐study with daily exposure exudate in the olfactory epithelium is observed in 10 of 24 rats. A NAEC of 10 ml/m3 is extrapolated. 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. Taking into consideration exposure of rats took place 7 days a week and no chronic study is available, it is assumed, that the chronic NAEC is 5 ml/m3. As olfactory epithelium is the target tissue, according to the empirical approach, the MAK‐value is reduced to 2 ml/m3. The assignment to Peak Limitation Category I, because local effects are critical, and the excursion factor of 2 are confirmed. As there are no developmental toxicity studies, the assignment to Pregnancy Risk Group D is confirmed

3‐Iodo‐2‐propynyl butylcarbamate (IPBC) : MAK Value Documentations, 2011

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated 3‐iodo‐2‐propynyl butylcarbamate (IPBC) to establish a maximum concentration at the workplace (MAK value), considering all toxicity endpoints. Available unpublished study reports and publications are described in detail. IPBC is irritating to the eyes and respiratory tract and has a skin sensitizing potential. New data have substantiated the previous designation with “Sh”. In a 5‐day aerosol inhalation study in rats, hyperplasia, squamous metaplasia and necrosis of the underlying cartilage of the larynx were observed at 1 mg/m3 and above. These effects were observed to an increased extent in the 13‐week study, in which the NOAEC was 0.23 mg/m3 and the LOAEC 0.3 mg/m3. Since the laryngeal irritation is the most sensitive endpoint, a MAK value of 0.1 mg/m3 (0.01 ml/m3) is established. IPBC has been attributed Peak Limitation Category I for local effects with an excursion factor of 2, since there was no direct sensory irritation but rather a tissue alteration and the NOAEC of the 5‐day study was 3 times the MAK value. In rats IPBC caused no tumours in an oral 2‐year carcinogenicity study. Increased number of liver adenomas in male mice might have been caused by liver enzyme induction. Available studies in vitro and in vivo provided no evidence of a specific genotoxic effect. Therefore IPBC is not classified as carcinogen or germ cell mutagen. In rats and mice, there was a sufficiently high difference between the oral NOAEL for developmental toxicity scaled to a concentration at the work place and the MAK value. Therefore IPBC is classified in Pregnancy Risk Group C. Skin contact will not significantly contribute to the systemic toxicity of 3‐iodo‐2‐propynyl butylcarbamate

n‐, sec‐, iso‐, tert‐Butylamin : MAK Value Documentation in German language, 2016

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 n‐, sec‐, iso‐ and tert‐butylamine, considering local and systemic toxicity as well as developmental toxicity. Daily exposure of rats to n‐butylamine for 14 days resulted in inflammation of respiratory epithelium at 17 ml/m3. 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, which would result in lowering the MAK‐value for n‐butylamine. However, workers reported no irritation at 1 to 2 ml n‐Butylamine/m3. Therefore, the MAK value of 2 ml/m3 is confirmed, also for sec‐ and iso‐butylamine due to similar structure, pKa and RD50 values. With tert‐butylamine the LOAEC of 66 ml/m3 in rats in a 13‐week study resulted in nasal tissue inflammation and liver weight increase. Following the empirical approach, the same MAK value of 2 ml/m3 is set for tert‐butylamine. As local effects might be or are critical, Peak Limitation Category I and an excursion factor of 2 and momentary value of 5 ml/m3 is assigned for all butylamine isomers. Developmental toxicity studies with n‐butylamine show that damage to the embryo or foetus is unlikely if the MAK value is observed and thus n‐butylamine is assigned to Pregnancy Risk Group C. Due to the lack of developmental toxicity studies, sec‐, iso‐ and tert‐butylamine are assigned to Pregnancy Risk Group D