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Testing dustiness of nanomaterials with a rotating drum
Piotr Sobiech s. 8
Nanotechnology is a fast-growing area in many industries. Therefore, research related to poten-tial risks (especially inhalation exposure) linked to the processes of production and handling of nanomaterials is even more important. Dustiness of nanomaterials is a major risk factor in inhalation exposure to airborne particles released from powdered nanomaterials. There are many methods for evaluating the dustiness of materials. Most of them use gravimetric analysis, which is insufficient to characterize dust released from nanomaterials. Since dustiness is a parameter that depends not only on the properties of a material, but also on the method of its determination, it is necessary to develop a standardized approach. This has been commissioned by the European Commission. This paper describes issues related to methods of testing dustiness, adapting existing methods and creating new methods for characterizing dust released from nanomaterials. It also describes a method of testing dustiness of nanomaterials with a small rotating drum. This method generates an aerosol under controlled conditions during drum rotation. Dust released during the process is analysed gravimetrically and by counting.
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Cyclophosphamide. Documentation of proposed values of occupational exposure limits (OEL)
Jan Gromiec s. 19
Cyclophosphamide (monohydrate) is a fine white crystalline odorless powder The substance liquefies and becomes an oily semisolid mass when water is removed. It darkens on exposure to light.
Cyclophosphamide an antineoplastic and im-munosuppressant agent. It is used to treat malignant lymphoma, multiple myeloma, leukemia, breast and ovarian cancer, neuroblastoma and malignat neoplasms of the lung. Cyclophosphamide is also used as an immunosuppressive agent to treat autoimmune disorders such as rheumatoid arthritis, psoriatic arthritis and nephrotic syndrome (a kidney disorder) in children. It is increasingly being used as an inmunosuppressive agent following organ (kidney, bone marrow) transplantation. The drug may be administered orally in the form of tablets or intravenously following dissolution ex tempore in aqua for injections. It may also be used for perfusion of cancer-affected organs. In chemotherapy, it may be used alone, but more frequently is used concurrently or sequentially with other anticancer drugs.
During manufacture of cyclophosphamide, skin and the respiratory system are the main routes of exposure. Since skin is the most important route of exposure of medical personnel, most of the reported exposure data include surface concentration of the compound in locations where the drug is prepared for treatment and cyclophosphamide concentration on the skin and in urine of the personnel.
No data on occupational exposure during production of cyclophosphamide in Poland are available. It is not known whether cyclophosphamide is manufactured in Poland. According to the information in the Central Register of Exposure to Cancerogenic Compounds, Mix-tures and Technological Processes, 1476 persons were occupationally exposed to cyclophosphamide in 2001 in Poland. In 2010, there were 5077 oncological nurses (incomplete data, 12 out of 16 voivodships).
Oral LD50 for cyclophoshamide was 180 mg/kg bw for rats and 137 mg/kg bw for mice. In mice, rats and dogs the predominant haematologic effect was leucopaenia. Depression in bone marrow and thrombocytes was also reported. Cyclophosphamide causes a marked necrosis of the bladder and of the tubular and pelvic epithelium in mice, rats and dogs; moderate damage in liver was also observed. Toxicity data for humans are derived mostly from findings in patients treated with cyclophosphamide. The predominant haematological effect of cyclo-phosphamide is leucopaenia. Acute toxicity of cyclophosphamide may lead to bone marrow damage, hemorrhagic cystitis and cardiomyopathy. Cyclophosphamide induced cardiotoxicity may be pronounced as changes in blood pressure, abnormal EKG, arhythmia leading to secondary cardiomyopathy with lowered left ventricular ejection fraction (LVEF) and heart failure leading in isolated cases even to death.
The most frequent side effect of treatment of autoimmune inflammatory diseases (e.g., systemic lupus erythematosus, systemic vasculitis, scleroderma, rheumatoid arthritis, Wegener's granulomatosis) is toxicity to the urinary bladder. Incidence of hemorrhagic cystitis was in the range 12 – 41% in patients receiving orally more than 100 g of the drug over 30 months and more. The bladder toxicity of cyclophospha-mide is caused by the formation of acrolein, which is its metabolite; hemorrhagic cystitis is, however, extremely rare following intravenous administration. Another symptoms in cyclo-phosphamide-treated patients are sodium and water retention, pulmonary fibrosis, visual blurring, nail pigmentation but the causative role of cyclophosphamide in these effects is, however, not well established.
Genotoxicity of cyclophosphamide has been confirmed in many tests in vivo, in vitro and on cultured animal models. Many studies have investigated the cytogenicity of cyclophospha-mide in newts, rodents, dogs and non-human primates giving consistently positive results. There are numerous reports of DNA-adduct formation by cyclophosphamide in humans.
The International Agency for Research on Cancer (IARC) has announced that there is sufficient evidence in humans for the carcinogenicity of cyclophosphamide. Cyclophosphamide causes cancer of the bladder and acute myeloid leukemia. There is also sufficient evidence in laboratory animals for the carcinogenicity of cyclophosphamide. Cyclophosphamide has been classified as carcinogenic to humans (Group 1).
In the European Union, cyclophosphamide has been classified as carcinogenic category 1.A and mutagenic category 2.B.
Cyclophosphamide has an influence on reproducibility in humans both during treatment and immediately afterwards. It causes fertility impairment and menstrual disorders. Cyclophosphamide is teratogenic to many animal species including rats, mice, rabbits and primates. It is responsible for a variety of muscu-loskeletal and other malformations and an increased number of resorptions, The type and frequency of malformations are strictly dose- and time-dependent. It is harmful to embryos and may lead to abortions. Exposure to cyclo-phosphamide in the first trimester of pregnancy may cause numerous congenital anomalies in fetuses, musculoskeletal malformations and deformations of limbs.
Cyclophosphamide may be absorbed by inhalation, ingestion, from skin contact or from peritoneum. In the case of occupational exposure of health professionals, skin is considered the main route of exposure.
Both in Poland and in other countries, neither occupational exposure level (OEL) in work-place air nor biological exposure index (BEI) has been established for occupational exposure to cyclophosphamide.
The proposed OEL value for cyclophosphamide has been derived from its carcinogenicity to laboratory animals, namely from a cancer slope factor (CSF) of 0.57 (mg/kg/day)–1 for bladder cancer, calculated from lifetime oral exposure of rats. The mean dose for 1 ∙ 10-4 excess lifetime cancer risk would be 1.754 ∙ 10-4 (mg/kg/day)–1, which in the condition of occupational inhalation exposure is equivalent to air concentration 0.01 mg/m³ and this value is proposed as Time Weighted Average (TWA) OEL. The proposed OEL should protect employees against leukemia and reproductive toxicity, too. The proposed biological exposure index (BEI) is 1 μg of cyclophosphamide in a 24-hr urine sample. There are no grounds for es-tablishing short-term exposure limit (STEL).
Labelling the substance with “Carc. 1A” (carcinogen category 1A), “Skóra” (substance can pene
trate skin) and “Ft” (substance harmful to fetus) has been proposed.
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Methotrexate – inhalable fraction Documentation of proposed values of occupational exposure limits (OELs)
MAŁGORZATA KUPCZEWSKA-DOBECKA s. 75
Methotrexate (MTX) is a structural analogue of folic acid. This compound is solid at room temperature; it is a yellowish-orange, crystalline powder with a slight odor characteristic of aromatic compounds. Methotrexate is a cytostatic drug administered in infusion or orally; it is a folic acid antagonist.
Occupational exposure to cytotoxic drugs takes place at two stages of their application, i.e., during manufacturing processes and during their use in daily practice of medical wards, especially those which treat cancer patients. In Poland, methotrexate is not produced, and there are currently no data on the number of people exposed to its action in health care, because the value of the maximum concentration of the substance in the workplace has not been set. NIOSH in 2004 estimated that the number of persons occupationally exposed to cytotoxic drugs and other dangerous drugs in the USA exceeded 5 million.
The main effects of methotrexate after intragastric, intramuscular or intravenous admin-istration include myelosuppression, hepatotoxicity and impaired fertility. In terms of exposure by inhalation, methotrexate can irritate the eyes and mucous membranes of the nose. This substance is classified as irritating to the skin and eyes, category 2. Contact with the skin was found to be the most important risk factor for medical personnel exposed to cytotoxic drugs. The most frequently reported skin symptoms were associated with removal of methotrexate powder or solutions and in contact with the excrement of patients undergoing chemotherapy.
Methotrexate induced genetic damage of deoxyribonucleic acid (DNA) in micronucleus, comet and hprt gene mutation tests among workers employed in a plant manufacturing methotrexate. Chromosomal damage was found in the bone marrow of patients treated with methotrexate. Animal studies confirmed methotrexate-induced genotoxicity.
On the basis of available data, the International Agency Research on Cancer (IARC) concluded that there was no evidence of a carcinogenic effect of methotrexate in humans and animals (group 3). In a group of patients treated with methotrexate, there was no conclusive evidence of an increased risk of cancer. Methotrexate was not carcinogenic in chronic animal studies after intragastric, intraperitoneal or intravenous administration.
Methotrexate affects fertility in humans, both during treatment and for a short time after-wards. With respect to the sexual function and fertility, category 2 is the present recommended methotrexate harmonized classification for re-productive toxicity; however, with respect to the development of the offspring, it is category 1A.
It is proposed to determine the MAC values for the inhalable fraction of methotrexate at the level of 0.001 mg/m³. Determination of the limit value in the working environment for methotrexate imposes on employers an obligation to monitor the concentration of this chemotherapeutic agent in the working environment. It will also make it possible to assess actual exposure of medical personnel to this substance. The authors found basis for determining short-term ( STEL ) and permissible concentrations in biological material (DSB) of methotrexate. It is also proposed to use the "skin" label in the list of occupational exposure limit because absorption through the skin may be as important as inhalation. Using the letters " Ft " – toxic to the fetus – is also proposed.
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Thiram. Determination in workplace air
Elżbieta Dobrzyńska, Agnieszka Woźnica s. 120
Introduction
Thiram is a colorless, combustible and non-volatile solid substance with a characteristic odor, practically insoluble in water. In Poland, thiram is used mainly as an agricultural chemical active ingredient of plant protection products (mainly fungicides) and as an accelerator in the chemical industry. In medicine or cosmetology, it is used as a sunscreen and antifungal agent. The mechanism of toxicity of thiram is multidirectional. The main symptoms of poisoning with thiram are headache, nausea and vomiting, heart rhythm disturb-ances, and difficulty in breathing. Often, as a result of acute poisoning conjunctivitis, bronchitis, urticaria and skin eruptions develop.
Aim of the study
The aim of this study was to develop and validate a sensitive method for determining concentrations of thiram in the working environment in the range of 1.10 –2 MAC values in accordance with the requirements of PN-EN-482.
Methods
The tests were performed with high performance liquid chromatography (HPLC). A
liquid chromatograph of Agilent Technologies equipped with a diode array detector (DAD) and an autosampler was used. In the test, an Ultra C18 column (250 x 4.6 mm, dp = 5 mm) with a 10 x 4.0 mm precolumn (Restek, USA) was used.
Results The method was based on passing air through a polypropylene filter, elution of thiram deposited on the filter with acetonitrile and its further chromatographic analysis. As a result, the conditions of thiram sampling in workplace air and its analysis in the concentration range of 0.05 - 1 mg/m3 with HPLC were determined. Validation of the method was carried out in accordance with European Standard EN 482: 2012. The following validation parameters were determined: measuring range: 3.6 - 72 mg/ml (0.05 -1 mg/m³ for air samples of 360 L), limit of detection (LOD) of 1.29 ng/ml,the limit of quantification LOQ = 3.86 ng / ml, the overall accuracy of the method 5.19%, the relative total uncertainty of the method 11.38%. The correlation factor R that characterizes the linearity of the calibration curve for the thiuram was 0.9999.
Conclusions
The analytical method described in this paper makes it possible to selectively determine thiram in workplace air in the presence of aniline; 1,3-butadiene and styrene at concentrations from 0.05 mg/m³ (1/10 MAC value). The method is precise, accurate and meets the criteria for procedures for measuring chemical agents listed in EN 482:2006. The developed method of determining thiram has been recorded as an analytical procedure (see Appendix).
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The activity of the Interdepartmental Commission for Maximum Admissible Concentrations and Intensities for Agents Harmful to Health in the Working Environment in 2014
Jolanta Skowroń
In 2014, the Commission met at three sessions, in which 11 documentations for recommended exposure limits of chemical substances were discussed. Moreover, the Commission discussed:
– justification for proposing amendments to the MAI (NDN) for electromagnetic fields in the context of the implementation of the Directive of the European Parliament and of the Council 2013/35/EC and
– the position of the Group of Experts on Noise on the results of tests and procedures for measuring low-frequency and ultrasound noise.
The Commission suggested to the Minister of Labour and Social Policy the following changes in the list of MAC values:
– adding six new chemical substances to the list of MAC values: tert-butyl ether, propano-1,3-sultone (Carc. 1B), methotrexate (inhalable fraction), diacetyle, cyclophosphamide (Carc. 1A), 2-nitropropane (Carc. 1B)
– changing MAC values for 4 chemicals: acrylamide (Carc. 1B), chlorophenylmethane, hydrazine (Carc. 1B), 2-methyl-2,4-pentanediol
– adding to the list of MAC in Annex 1 of Part A a "Comments" column and writing "skin" to include information that some substances may be extensively absorbed by the skin.
The Commission has adopted documentation for electromagnetic fields with a frequency range from 0 Hz to 300 GHz in the context of the implementation of the Directive of the European Parliament and of the Council 2013/35/EC on the minimum requirements for the protection of health and safety requirements regarding the exposure of workers to the risks arising from physical agents (electromagnetic fields) (XXth individual Directive within the meaning of art. 16 paragraph. 1 of Council Directive 89/391/EEC) and repealing Directive 2004/40/EC (OJ. office. EU L 179 of 29.06.2013, 1-21) and has submitted it to the Ministry of Labour and Social Policy in order to further legislative work. According to the Commission, ultrasonic noise is more harmful than low-frequency noise, so there is no need to set separate values of maximum intensity for low-frequency noise and infrasounds. The Commission also adopted a procedure for measuring ultrasonic noise, taking into account measurement uncertainty and factors that affect the result. Four issues of the "Principles and Methods of Assessing the Working Environment " were published in 2014. The following were published: 14 methods of determining chemical concentrations in the working environment, 9 documentation of occupational exposure limit and two articles. In addition, the Commission’s experts prepared materials for the 9th edition of the Commission's "Harmful factors in the working environment - limit values". Three sessions of the Commission are planned for 2015. MAC values for 10 chemicals substances will be discussed at those meetings. The Commission and the Group of Experts will continue working on adapting the Polish list of occupational exposure limit values to the draft Directive setting the fourth list of indicative occupational exposure limit values, on proposals for binding values and on work being done at SCOEL.
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