Metotreksat – frakcja wdychalna : dokumentacja proponowanych dopuszczalnych wielkości narażenia zawodowego

• Autorzy: Kupczewska-Dobecka M.

Warianty tytułu

EN

Methotrexate – inhalable fraction : documentation of proposed values of occupational exposure limits (OELs)

• Języki publikacji: PL

Abstrakty

PL

Metotreksat (MTX) jest strukturalnym analogiem kwasu foliowego. Związek jest w temperaturze pokojowej ciałem stałym występującym w formie jasnożółtopomarańczowego krystalicznego proszku o lekkim zapachu, charakterystycznym dla związków aromatycznych. Metotreksat jest stosowany jako lek cytostatyczny podawany w infuzjach lub doustnie, należący do antagonistów kwasu foliowego. O zawodowym narażeniu na cytostatyki można mówić na dwóch etapach ich zastosowania, tj. podczas procesów wytwarzania chemioterapetyków oraz podczas ich stosowania w codziennej praktyce leczniczej oddziałów szpitalnych, przede wszystkim tych, na których leczeni są pacjenci chorujący na choroby nowotworowe. W Polsce metotreksat nie jest produkowany i obecnie brak jest danych o liczbie osób narażonych na jego działanie w placówkach służby zdrowia, ponieważ nie zostały ustalone wartości najwyższych dopuszczalnych stężeń tej substancji w środowisku pracy. W NIOSH w 2004 r. oszacowano, że liczba osób narażonych zawodowo w USA na cytostatyki i inne leki niebezpieczne przekracza 5 mln. Główne skutki działania metotreksatu po podaniu: dożołądkowym, domięśniowym lub dożylnym, obejmują: zahamowanie czynności szpiku kostnego, działanie hepatotoksyczne oraz zaburzenia płodności. W warunkach narażenia inhalacyjnego metotreksat może podrażniać oczy i błony śluzowe nosa. Substancja została zaklasyfikowana jako drażniąca na skórę i oczy kategorii 2. Kontakt ze skórą uznano za najważniejszy czynnik ryzyka dla personelu medycznego narażonego na cytostatyki. Najczęściej zgłaszane objawy skórne dotyczyły kontaktu z rozlanym roztworem zawierającym metotreksat lub wysypanym z opakowania produktem, w czasie jego usuwania oraz kontaktu z ekskrementami pacjentów poddawanych chemioterapii. U pracowników, zatrudnionych w zakładzie produkującym metotreksat, związek powodował uszkodzenia genetyczne kwasu dezoksyrybonukleinowego (DNA) w testach: mikrojądrowym, kometowym i mutacji genowych hprt. Uszkodzenia chromosomów stwierdzono w szpiku kostnym pacjentów leczonych metotreksatem. Genotoksyczność wywoływaną przez metotreksat potwierdzono na podstawie wyników badań na zwierzętach. Na podstawie dostępnych danych w Międzynarodowej Agencji ds. Badań nad Rakiem (IARC) stwierdzono, że brak jest dowodów na działanie rakotwórcze metotreksatu u ludzi i zwierząt (grupa 3.). W grupie chorych leczonych metotreksatem nie uzyskano jednoznacznych dowodów potwierdzających zwiększone ryzyko nowotworów. Metotreksat nie wykazywał działania rakotwórczego w przewlekłych badaniach na zwierzętach po podaniu: dożołądkowym, dootrzewnowym oraz dożylnym. Metotreksat wpływa na rozrodczość u ludzi zarówno w okresie leczenia, jak i przez krótki czas po jego zakończeniu. Obecnie rekomenduje się zharmonizowaną klasyfikację metotreksatu pod kątem szkodliwego działania na rozrodczość i ze względu na funkcje rozrodcze oraz płodność do kategorii 2., tj. substancji, co do których podejrzewa się, że działają szkodliwie na rozrodczość ludzi i ze względu na rozwój potomstwa do kategorii 1.A, tj. substancji działających szkodliwie na rozrodczość ludzi. Podstawą ustalenia wartości NDS dla metotreksatu były następujące dane: 1. Metotreksat wykazuje bezprogowe działanie genotoksyczne, które może wystąpić na każdym poziomie narażenia. Na podstawie danych u ludzi ustalenie zależności dawka-odpowiedź nie jest możliwe, jak również nie jest to możliwe przez ekstrapolację wyników z badań na zwierzętach. 2. Producenci metotreksatu ustalili dopuszczalne poziomy narażenia zawodowego na poziomie 0,0003 ÷ 0,0025 mg/m3. 3. Na podstawie przedstawionych klasyfikacji (IPCS, NIOSH, ASHP, IACP) metotreksat powinien mieć wartość dopuszczalnego narażenia zawodowego na poziomie < 0,01 mg/m3. Wartość tę przyjęto za podstawę do ustalenia wartości najwyższego dopuszczalnego stężenia (NDS) i zastosowano arbitralnie współczynnik niepewności równy 10, uwzględniając skutki odległe, wynikające z działania metotreksatu, tj. działanie genotoksyczne i szkodliwe działanie na rozrodczość u ludzi, zarówno na płodność, jak i rozwój potomstwa. Zaproponowano przyjęcie wartości NDS dla frakcji wdychalnej metotreksatu na poziomie 0,001 mg/m3. Ustalenie wartości dopuszczalnej w środowisku pracy dla metotreksatu nałoży na pracodawców obowiązek monitorowania stężenia tego cytostatyku w środowisku pracy i pozwoli na ocenę rzeczywistego narażenia personelu medycznego na tę substancję. Nie ma podstaw merytorycznych do ustalenia wartości najwyższego dopuszczalnego stężenia chwilowego (NDSCh) i wartości dopuszczalnego stężenia w materiale biologicznym (DSB) metotreksatu. Należy zastosować także oznakowanie „skóra”, ponieważ wchłanianie substancji przez skórę może być podobnie istotne, jak przy narażeniu drogą oddechową, a także oznakowanie literami „Ft” – substancja działająca szkodliwie na płód.

EN

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 administration 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 afterwards. With respect to the sexual function and fertility, category 2 is the present recommended methotrexate harmonized classification for reproductive toxicity; however, with respect to the development of the offspring, it is category 1A. The MAC-TWA value for methotrexate was set on the basis of the following: 1. Methotrexate is genotoxic without a threshold, which may occur at any level of exposure. Based on the data in humans, it is not possible to determine the dose-response; this is not possible by extrapolation of results from animal studies, either. It is not possible to propose the MAC value on the basis of the smallest oral therapy dose because in 10% to 37% of patients methotrexate results in adverse effects after low therapeutic doses. Myelosuppression and toxic effects on mucous membranes depend on the dose of methotrexate and the time of exposure; the critical dose is > 2 - 10- 8 mol/L plasma. 2. Manufacturers of methotrexate established occupational exposure levels at 0.0003 – 0.0025 mg/m3. In 1988, OSHA arbitrarily established a target concentration level of 0.04 mg/m3 (40 μg/m3) for the purposes of air monitoring. 3. On the basis of the classification (IPCS, NIOSH, ASHP, IACP), methotrexate should have a permissible occupational exposure value of < 0.01 mg/m3. This value was taken as a basis for determining the maximum admissible concentration (MAC ); the arbitrary uncertainty factor of 10 was used, taking into account long-term consequences, resulting from the action of methotrexate, i.e., genotoxicity and reproductive toxicity in humans: the effect on both the fertility and development of the offspring in humans. 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.

Słowa kluczowe

PL

metotreksat; cytostatyki; narażenie zawodowe

EN

methotrexate; antineoplastics drugs; occupational exposure

• Wydawca: Centralny Instytut Ochrony Pracy - Państwowy Instytut Badawczy
• Czasopismo: Podstawy i Metody Oceny Środowiska Pracy
• Rocznik: 2015
• Tom: Nr 1 (83)
• Strony: 73--118
• Opis fizyczny: Bibliogr. 216 poz., tab.

Twórcy

autor

Kupczewska-Dobecka M.

• Instytut Medycyny Pracy im. prof. dr. med. Jerzego Nofera 91-348 Łódź ul. św. Teresy od Dzieciątka Jezus 8 90-151 Łódź, ul. J. Muszyńskiego 1

Bibliografia

• 1.Alvarez-Figueroa M.J., Delgado-Charro M.B., Blanco-Mendez J. (2001) Passive and ionophoretic transdermal penetration of methotrexate. Int. J. Pharm. 212, 101–7.
• 2.American Pharmaceutical Partners. INC Safety Data Sheet (2005) [https://secure.mypss.com/cat- MaintDataServlet?existingFileId=2473].
• 3.ASHP, American Society of Health-System Pharmacists (Amerykańskie Stowarzyszenie Farmaceutów), (1990) Technical assistance bulletin on handling cytotoxic and hazardous drugs, drug distribution and control. Preparation and Handling- Technical Assistance Bulletin 49–64.
• 4.Bailin P.L., Tindall J.P., Roenigk H.H., Jr., Hogan M.D. (1975) Is methotrexate therapy for psoriasis carcinogenic? A modified retrospective-prospective analysis. J. Am. Med Assoc. 232, 359–362.
• 5.Banerjee A., Benedict W.F. (1979) Production of sister chromatid exchanges by various cancer chemotherapeutic agents. Cancer Res. 39, 797–799.
• 6.Barker J., Horn E.J., Lebwohl M., Warren R.B., Nast A., Rosenberg W., Smith C. (2011) Assessment and management of methotrexate hepatotoxicity in psoriasis patients. Report from a consensus conference to evaluate current practice and identify key questions toward optimizing methotrexate use in the clinic. J. European Academy of Dermatol. And Venerol. 25, 758–764.
• 7.Bawle E.V., Conard J.V., Weiss L. (1998) Adult and two children with fetal methotrexate syndrome. Teratology 57(2), 51–55.
• 8.Benedict W.F., Banerjee A., Gardner A., Jones P.A. (1977) Induction of morphological transformation in mouse C3H/10T% clone 8 cells and chromosomal damage in hamster A (Tl )Cl-3 cells by cancer chemotherapeutic agents. Cancer Res. 37, 2202– 2208.
• 9.BEN VENUE LABORATORIES, INC. Safety Data Sheet.
• 10.[http://www.bedfordlabs.com/content/dam/internet/opu/bedfordlabs/com_EN/documents/products/Methotrexate/MethotrxateRev307].
• 11.Berner-Strzelczyk A. (2012) Leki wziewne – zalety i wady. Aptekarz Polski 75/53 [online].
• 12.Bischoff K.B., Dedrick R.L., Zaharko O.S. (1970) Preliminary model for methotrexate pharmacokinetics. J. Pharm. Sei. 59, 149–154.
• 13.Blackburn W.K., Alarcon G.S. (1989) Impotence in three rheumatoid arthritis patients treated with methotrexate. Arthritis Rheum 32, 13412.
• 14.Bleyer W.A. (1977) Methotrexate: clinical pharmacology, current status and therapeutic guidelines. Cancer Treat Rev. 4, 87–101.
• 15.Borsi J.D., Sagen E., Romslo I., Moe P.J. (1990) Comparative study of the pharmacokinetics of 7- hydroxymethotrexate after administration of methotrexate in the dose range of 0.5 g to 33.5 g/m2 in children with acute lymphoblastic leukemia. Med. Pediatr. Oncol. 18, 217.
• 16.Breithaupt H., Kuenzlen E. (1982) Pharmacokinetics of methotrexate and 7-hydroxymethotrexate following infusions of high-dose methotrexate. Cancer Treat Rep. 66(9), 1733–41.
• 17.Bremnes R.M., Smeland E., Huseby N.E, Eide T.J., Aarbakke J. (1991) Acute hepatotoxicity after highdose methotrexate ad-ministration to rats. Pharmacol. Toxicol. 69, 132.
• 18.Brumen V., Horvat D. (1996) Work environment influence on cytostatics-induced genotoxicity in oncologic nurses. Am. J. Ind. Med. 30, 67–71.
• 19.Buckley L.M., Bullaboy C.A., Leichtman L., Marquez M. (1997) Multiple congential anomalies associated with weekly lowdose methotrexate treatment of the mother. Arthritis Rheum 40(5), 971– 973.
• 20.Burgaz S., Karahalil B., Canh Z., Ancel G., Anzion R.B.M., Bos R.P., Huttner E. (2002) Assessment of genotoxic damage in nurses occupationally exposed to antineoplastics by the analysis of chromosomal aberrations. Human & Experimental Toxicology 21, 129–135.
• 21.Calvert A.H., Bondy P.K., Harrap K.R. (1977) Some observations on the human pharmacology of methotrexate. Cancer Treat. Rep. 61, 1647–1656.
• 22.Chabner B.A., Myers C.E., Coleman C.N., Johns D.G. (1975) The clinical pharmacology of antineoplastic agents (first of two parts.) New Eng. J. Med. 292, 1107–1113.
• 23.Chamberlin A.A., Cheung A.P.K., Lim P. (1976) Methotrexate [W:] Analytical profiles of drug substances. New York, Academic Press vol. 5, 283– 306.
• 24.Chatterjee D.J., Li W.Y., Koda R.T. (1997) Effects of vehicles and penetration enhancers on the in vitro and in vivo percutaneous absorption of methotrexate and edatrexate through hairless mouse skwsp. Pharm. Res. 14(8) 1058–65.
• 25.Chelab K.G., Majeed S. Kh. (2009) Methotrexateinduced histopatological changes in the kidneys of mice. Iraqi J. Vet. Sci. 23 suppl. II, 219–222.
• 26.Chu W.C., Hon C.Y., Danyluk Q., Chua P.P.S., Astrakianakis G. (2011) Pilot assessment of the antineoplastic drug contamination levels in British Columbian hospitals pre- and post-cleaning. J. Oncol. Pharm. Practice 18(1) 46–51.
• 27.Clarysse A.M., Cathey W.J., Cartwright G.E., Wintrobe M.M. (1969) Pulmonary disease complicating intermittent therapy with methotrexate. J. Am. Me. Assoc. 209, 1861–1864.
• 28.Cohn J.R., Cohn J.B., Fellin F., Cantor R. (1993) Systemic anaphylaxis from low dose methotrexate. Ann. Alergy 70, 384–5.
• 29.Collins K., Aspey H., Todd A., Satavanan V., Rynne M., Kelly C. (2008) Methotrexate pneumonitis precipitated by switching from oral to parenteral administration. Rheumatology 47, 109 –110.
• 30.Corona-Rivera J.R., Rea-Rosas A., Santana-Ramirez A., Costa-Leon J., Hernandez-Rocha J., Miguel-Jimenez K. (2010) Holoprosencephaly and genitourinary anomalies in fetal methotrexate syndrome. Am. J. Med. Genet A. 152A(7), 1741–1746.
• 31.Craig S.A., Rosenberg E.W. (1971) Methotrexateinduced carcinoma? Arch. Dermatol. 103, 505–506.
• 32.Criswell K.A., Krishna G., Zielinski D., Urda G.A., Juneau P., Bulera S., Bleavins M.R. (2003) Validation of a flow cytometric acridine orange micronuclei methodology in rats. Mutat. Res. 25, 528(1–2), 1–18.
• 33.Custer A.P., Freeman-Narrod M., Narrod S.A. (1977) Hepatotoxicity in Wistar rats following chronic methotrexate administration. A model of human reaction. J. Natl. Cancer Inst. 58, 1011– 1017.
• 34.Davis H.L. Jr, Prout M.N., McKenna P.J., Cole D.R., Korbitz B.C. (1973) Acute leukemia complicating metastatic breast cancer. Cancer 31, 543– 546.
• 35.Del Campo M., Kosaki K., Bennett F.C., Jones K.L. (1999) Developmental delay in fetal aminopterin/ methotrexate syndrome. Teratology 60(1), 10–12.
• 36.Delmonte L., Jukes T.H. (1962) Folic acid antagonists in cancer chemotherapy. Pharmacol. Rev. 14, 91–135.
• 37.Deng H., Zhang M., He J., Wu W., Jin L., Zheng W., Lou J., Wang B. (2005) Investigating genetic damage in workers occupationally exposed to methotrexate using three genetic end-points. Mutagenesis 20(5), 351–357.
• 38.DeSesso J.M., Jordan R.L. (1977) Drug-induced limb dysplasias in fetal rabbits. Teratology 15, 199– 212.
• 39.De Werk Neal A., Wadden R.A., Chiou W.I. (1983) Exposure of hospital workers to airborne antineoplastic agents. Am. J. Hosp. Pharm. 40, 597–601.
• 40.Diniz E.M., Corradini H.B., Ramos J.L., Brock R. (1978) Efeitos sobre o concepto do metotrexato (ametopterina) administrado a mae. Apresentacao de caso. [Effect, on the fetus, of methotrexate (amethopterin) administered to the mother. Presentation of a case]. Rev. Hosp. Clwsp. Fac. Med. Sao Paulo 33(6), 286–290.
• 41.EBEWE (2007) Charakterystyka produktu leczniczego Methotrexat-Ebewe. 7.12.2007.
• 42.Eherts D. (2004) Control banding from the pharma perspective. Staying ahead of the regulation, society of chemical hazard communication. SCHC FALL 2004 Meeting, October 26–27, Arlington, VA.
• 43.El-Beheiry A., El-Mansy E., Kamel N., Salama N. (1979) Methotrexate and fertility in men. Arch. Androl. 3(2), 177–179.
• 44.Epstein E.H., Jr. Croft J.O. (1969) Cirrhosis following methotrexate administration for psoriasis. Arch. Dermatol. 100, 531–534.
• 45.Epstein S.S., Arnold E., Andrea J., Bass W., Bishop Y. (1972) Detection of chemical mutagens by the dominant lethal assay in the mouse. Toxicol. Appl. Pharmacol. 23, 288–325.
• 46.Ercan I., Cakir B.O., Basak T., Ozbal E.A., Sahin A., Balci G., Turgut S. (2006) Effects of topical application of methotrexate on nasal mucosa in rats. A preclinical assessment study. Otolaryngology-Head and Neck Surgery 13, 751–755.
• 47.Erttmann R., Bielack S., Landbeck G. (1985) Kinetics of 7-hydroxymethotrexate after high-dose methotrexate therapy. Cancer Chemother. Pharmacol. 15, 101.
• 48.Feldkamp M., Care J.C. (1993) Clinical teratology counseling and consultation case report: low dose methotrexate exposure in the early weeks of pregnancy. Teratology 47, 533–539.
• 49.Ferguson F.C., Jr. Thiersch J.B., Philips F.S. (1950) The action of 4-amino-N10-methylpteroylglutamic acid in mice, rats, and dogs. J. Pharmacol. Exp. Ther. 98, 293–299.
• 50.Fermion Oy, Safety Data Sheet (2013) Finlandia [http://www.fermion.fi/Global/Fermion/Fermionin%20uusi%20verkkosivu/MSDS/Methotrexate%20diNa]pdf.
• 51.Flament-Durand J., Ketelbant-Balasse P., Maurus R., Regnier A., Spehl M. (1975) Intracerebral calcifications appearing during the course of acute Iymphocytic leukemia treated with methotrexate and X rays. Cancer 35, 319–325.
• 52.Fransman W., Huizer D., Tuerk J., Kromhout H. (2007) Inhalation and dermal exposure to eight antineoplastic drugs in an industrial laundry facility. Int. Arch. Occup. Environ. Health 80, 396–403.
• 53.Florida L., Pietropaolo A.M., Tavazzani M., Rubino F.M., Colombi A. (1999) High-performance liquid chromatography of methotrexate for environmental monitoring of surface contamination in hospitals departments and assessment of occupational exposure. J. Chromatography B 726, 95–103.
• 54.Freeman-Narrod M., Narrod S., Custer A.P. (1974) Toxicity of methotrexate in C57/BI mice. In fluence of tolerance and age (abstract 2093). Fed. Proc. 33, 582.
• 55.Friese C.R., Himes-Ferris L., Frasier M.N., McCullagh M., Griggs J. (2012) Structures and processes of care in ambulatory oncology settings and nursereported exposure to chemotherapy. BMJ Qual. Sa. 21, 753–759.
• 56.Fuskevag O.M., Kristiansen C., Lindal S., Aarbakke J. (2000) Maximum tolerated doses of methotrexate and 7-hydroxy-methotrexate in a model of acute toxicity in rats. Cancer Chemother. Pharmacol. 46, 69–73.
• 57.Galwas M., Pośniak M. (2006) Kryteria oceny narażenia zawodowego na niebezpieczne substancje farmaceutyczne. Podstawy i Metody Oceny Środowiska Pracy 2(52), 5–16.
• 58.GESTIS-Stoffdatenbank.: 4-Amino-N10-methylpteroylglutamic acid. IFA [http://gestis.itrust.de/nxt/gateway.dll/gestis_de/490067.xml?f=templates$fn=document-frameset.htm$3.0].
• 59.Gilani S.T.A., Khan D.A., Khan F.A., Ahmed M. (2012) Adverse effects of low dose methotrexate in rheumatoid arthritis patients. J. of the College of Physicians and Surgeons Pakistan 22(2) 101–104.
• 60.Granzow J.W., Thaller S.R., Panthaki Z. (2003) Cleft palate and toe malformations in a child with fetal methotrexate exposure. J. Craniofac. Surg. 14(5), 747–748.
• 61.Greenspan E.M., Tung B.G. (1974) Acute myeloblastic leukemia after cure of ovarian cancer. J. Am. Med. Assoc. 230, 418–420.
• 62.Grunnet E., Nyfors A., Hansen K.B. (1977) Studies of human semen in topical corticosteroid-treated and in methotrexate-treated psoriatics. Dermatologica 154(2), 78–84.
• 63.Gunther Ev. (1970) Andrologische Untersuchungen bei der Antimetabolietentherapie der Psoriasis. Dermatol. Monatsschrift. 156, 498–502.
• 64.Gutin P.H., Green M.R., Bleyer W.A, Bauer V.L., Wiernik P.H., Walker M.D. (1976) Methotrexate pneumonitis induced by intrathecal methotrexate therapy. A case report with pharmokinetic data. Cancer 38, 1529–1534.
• 65.Jackson Re., Harrap K.R. (1973) Studies with a mathematical model of folate metabolism. Arch. Biochem. Biophys. 158, 827–841.
• 66.Johns D.G., Loo T.L. (1967) Metabolite of 4-amino- 4-deoxy-N10-methylpteroylglutamic acid (methotrexate). J. Pharm. Sci. 56, 356–359.
• 67.Hampel K.E., Kober B., Rösch O., Gerhartz H., Meinig K.H. (1966) The action of cytostatic agents on the chromosomes of human leukocytes in vitro (preliminary communication). Blood 27(6), 816– 823.
• 68.Hansen J., Olsen J.H. (1994) Cancer morbidity among Danish female pharmacy technicians. Scand. J. Work Environ. Health 20(1) 22–6A.
• 69.Harris C.C. (1971) Malignancy during methotrexate and steroid therapy for psoriasis. Arch. Dermatol. 103, 501–504.
• 70.Harrison B.R. (2001) Risks of handling cytotoxic drugs [W:] The chemotherapy source book [Red.] M.C. Perry. 3rd ed. Philadelphia, PA, Lippincott, Williams and Wilkins 566–582.
• 71.Healt Council of the Netherlande (2011) Methotrexate. Evaluation of the effects on reproduction, recommendation for classification. Subcommittee on the classification of reproduction toxix substances, a committee of the health council of the Nedherlands. Publication nr 2011/24. ISBN 978- 90-5549-856-7. Haga, The State Secretary of Social Affair and Employment.
• 72.Henderson E.S., Adamson R.H., Denham C., Oliverio V.T. (1965) The metabolic fate of tritiated methotrexate. I absorption, excretion, and distribution in mice, rats, dogs and monkeys. Cancer Res. 25(7), 1008–1017.
• 73.Herbold B., Buselmaier W. (1976) Induction of point mutations by different chemical mechanisms in the liver microsomal assay. Mutat. Res. 40, 73– 84.
• 74.Hersh E.M., Wong V., Henderson E.S., Rubin R. (1964) The acute hepatotoxic effects of methotrexate (MTX) therapy (abstract 101). Proc. Am. Assoc. Cancer Res. 5, 26.
• 75.Hlaing M., Malik U.F., Powell D. (2010) Methotrexate induced hypersensitivity pneumonitis. Review of literature with case report. Revista Romana de Reumatologie 19(1), 57–59.
• 76.HSDB, Hazardous Substance Data Bank (2010).
• 77.Hyoun S.C., Obican S.G., Scialli A.R. (2012) Teratogen update. Methotrexate. Birth defects research (part A) 94, 187–207.
• 78.IARC, Monographs on the evaluation of the carcinogenic risk of chemicals to humans (1981) Lyon, Some Antineoplastic and Immunosuppressive Agents, vol. 26.
• 79.Ibsen H.H. (1997) Methotrexat og graviditet. Ugeskr. Laeger 159(41), 6081–6083.
• 80.Jacobs S.A., Stoller R.G., Chabner B.A., Johns D.G. (1917) Dose-dependent metabolism of methotrexate in man and rhesus monkeys. Cancer Treat. Rep. 61, 651–656.
• 81.Johns D.G., Rutherford L.D., Leighton P.C., Vogel C.L. (1972) Secretion of methotrexate into human milk. Am. J. Obstet. Gynecol. 112(7), 978–980.
• 82.Jolly L.E., Jr. Fletcher H.P. (1917) The effect of repeated oral dosing of methotrexate on its intestinal absorption in the rat. Toxicol. Appl. Pharmacol. 39, 23–32.
• 83.Johnson F.E., Farr S.A., Mawad M., Woo Y.C. (1994) Testicular cytotoxicity of intravenous methotrexate in rats. J. Surg. Oncol. 55(3), 175–178.
• 84.Jordan R.L. (1973) Response of the rabbit embryo to methotrexate (abstract). Teratology 7, A–19.
• 85.Jordan R.L., Wilson J.G., Schumacher H.J. (1977) Embryotoxicity of the folate antagonist methotrexate in rats and rabbits. Teratology 15, 73–80.
• 86.Kasahara Y., Nakai Y., Miura D., Yagi K., Hirabayashi K., Makita T. (1992) Mechanism of induction of micronuclei and chromosome aberrations in mouse bone marrow by multiple treatments of methotrexate. Mutat. Res. 280(2), 117–28.
• 87.Kaslow R.A., Wisch N., Glass J.L. (1972) Acute leukemia following cytotoxic chemotherapy. J. Am. Med. Assac. 219, 75–76.
• 88.Keshava C., Keshava N., Whong W.Z., Nath J., Ong T.M. (1998) Inhibition of methotrexate-induced chromosomal damage by folinic acid in V79 cells. Mutat. Res. 2, 397(2), 221–228.
• 89.Kevekordes S., Gebel T.W., Hellwig M., Dames W., Dunkelberg H. (1998) Human effect monitoring in cases of occupational exposure to antineoplastic drugs. A method comparison. Occup. Environ. Med. 55, 145–149.
• 90.Koehler M., Koehler B. (1988) The effects of long term methotrexate therapy on the gonadal function and morphology. Endokrynol. Pol. 39(1), 33–40.
• 91.Kremer J.M., Lee J.K. (1986) The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis. Arthritis Rheum 29, 822– 831.
• 92.Kremer J.M., Phelps C.T. (1992) Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Update after a mean of 90 months. Arthritis Rheum 35, 138–145.
• 93.Kremer J.M. (2004) Toward a better understanding of methotrexate. Arthritis Rheum 50, 1370–82.
• 94.Kremer J.M. (1997) Safety, efficacy, and mortality in a long-term cohort of patients with rheumatoid arthritis taking methotrexate: followup after a mean of 13.3 years. Arthritis Rheum 40, 984–985.
• 95.Khera K.S. (1976) Teratogenicity studies with methotrexate, aminopterin, and acetylsalicylic acid in domestic cats. Teratology 14, 21–28.
• 96.Krahenmann F., Ostensen M., Stallmach T., Huch A., Chaoui R. (2002) In utero first trimester exposure to lowdose methotrexate with increased fetal nuchal translucency and associated malformations. Prenat. Diagn. 22(6), 489–490.
• 97.Kroese W.F.S. (1975) Cytostatic drugs [W:] Meyler's side effects of drugs. A survey of unwanted effects of drugs reported in 1972-1975 [Red.] M.N.G. Dukes. Amsterdam, Excerpta Medica vol. 8, 939–999.
• 98.Krogh Jensen M. (1967) Chromosome studies in patients treated with azathioprine and amethopterwsp. Acta Med. Scand. 182, 445–455.
• 99.Krogh Jensen M., Nyfors A. (1979) Cytogenetic effect of methotrexate on human cells in vivo. Comparison between results obtained by chromosome studies on bone-marrow cells and blood lymphocytes and by the micronucleus test. Mutat. Res. 64, 339–343.
• 100.Kromhout H., Hoek F., Uitterhoeve R., Huijbers R. (2000) Postulating a dermal pathway for exposure to antineoplastic drugs among hospital workers. Applying a conceptual model to the results of three workplace surveys. Ann. Occup. Hyg. vol. 44, 7, 551–560.
• 101.Kung F.T., Chang S.Y., Tsai Y.C., Hwang F.R., Hsu T.Y., Soong Y.K. (1997) Subsequent reproduction and obstetric outcome after methotrexate treatment of cervical pregnancy. A review of original literature and international collaborative follow-up. Hum. Reprod. 12(3), 591–595.
• 102.Lewis W.J., Walter J.F. (1979) Methotrexate-induced pulmonary fibrosis. Arch. Dermatol. 115, 1169–1170.
• 103.Levin L.I., Holly E.A., Seward J.P. (1993) Bladder cancer in a 39-year-old female pharmacist. J. Natl. Cancer. Inst. 85(13), 1089–1091.
• 104.Li F.P., Cassady J.R., Jaffe N. (1975) Risk of second tu mors in survivors of childhood cancer. Cancer 35, 1230–1235.
• 105.Lloyd M.E., Carr M., McElhatton P., Hall G.M., Hughes R.A. (1999) The effects of methotrexate on pregnancy, fertility and lactation. QJM 92, 55163.
• 106.Lu G., Jun H.W., Suh H. (1997) Percutaneous absorption and disposition studiem of methotrexate in rabbits and rats. Biopharm Drug Dispos. 18(5) 409– 22.
• 107.Luch-Bernal M.L., Cuesta-Herranz J., De Las Heras M., De Figueredo E., Umpierrez A., Fernandez M., Novalbos A., Casimiro C., Sastre J. (1997) Anaphylactic reaction to methotrexate. Allergy 52, 1150-1151.
• 108.Mader R.M., Rizovski B., Steger G.G., Wachter A., Kotz R., Rainer H. (1996) Exposure of oncologic nurses to methotrexate in the treatment of osteosarcoma. Arch. Environ. Health 51(4), 310–314.
• 109.Maier P., Schmid W. (1976) Ten model mutagens evaluated by the micronucleus test. Mutat. Res. 40, 325–388.
• 110.Mallipattu S.K., Ross M.J. (2011) Methotrexate in urine. Kidney International 80, 226, 111.Martindale, The extra pharmacopoeia (1977) [Red.] A. Wade. 27th ed., London, The Pharmaceutical Press 156–161.
• 112.Martinez Lopez J.A., Loza E., Carmona L. (2009) Systematic review on the safety of methotrexate in rheumatoid arthritis regarding the reproductive system (fertility, pregnancy, and breastfeeding). Clwsp. Exp. Rheumatol. 27(4), 678–684.
• 113.Matheson O., Brusick D., Carrano R. (1978) Comparison of the relative mutagenic activity for eight antineoplastic drugs in the Ames Salmonella/microsome and TK+/- mouse Iymphoma assays. Drug Chem. Toxicol. 1, 277–304.
• 114.Matsui H., Iitsuka Y., Suzuka K., Yamazawa K., Tanaka N., Seki K. (2003) Risk of abnormal pregnancy completing chemotherapy for gestational trophoblastic tumor. Gynecol. Oncol. 88(2), 104– 107.
• 115.McCormick J., Susten S.S., Rader J. , Freisheim J.H. (1979) Studies of a methotrexate binding protein fraction from L1210 lymphocyte plasma membranes. Eur. J. Cancer, 15, 1377–1386.
• 116.McCulloch J.L., Snyder D.S., Weinstein G.D., Friedland A., Stein B. (1976) Factor affecting human percutaneous penetration of methotrexate and its analogues in vitro. J. Invest. Dermatol. 66, 103–107.
• 117.McKenna K.E., Burrows D. (2000) Pulmonary toxicity in a patient with psoriasis receiving methotrexate therapy. Clwsp. Experimental. Dermatol. 25, 24–27.
• 118.Mcglashan A.J., Strong R.S., Middlemiss D., Hayes A.G., David A., Vodden M. (2007) Patent WO2007057714A2. Pharmaceutical compositions comprising methotrexate. Maj 2007[http://www.google.com/patents/WO2007057714A2?cl=en].
• 119.Medical research council working party on leukaemia in childhood (1975) Analysis of treatment in childhood leukaemia. 1. Predisposition to methotrexate- induced neutropenia after craniospinal irradiation. Br. Med. J. 11, 563–566.
• 120.Meditext – medical menagment (2014). Methotrexate and related agents. Thomson Reuters Inc. All Rights Reserved Data Base. 1987–2014.
• 121.Meijster T., Fransman W., Veldhof R., Kromhout H. (2006) Exposure to antineoplastic drugs outside the hospital environment. Ann. Occup. Hyg. 50(7) 657–664.
• 122.Melnyk J., Duffy D.M., Sparkes R.S. (1971) Human mitotic and meiotic chromosome damage following in vivo exposure to methotrexate. Clwsp. Genet. 2, 28–31.
• 123.Merger D., Tanguay C., Langlois E., Lefebvre M., Bussières J.-F. (2013) Environmental contamination with methotrexate in Canadian community pharmacies. J. Am. Pharm. Assoc. 53, 423–426.
• 124.Międzynarodowe Stowarzyszenie Farmaceutów Producentów, IACP-The International Academy of Compounding Pharmacists (2003) Hazard Alert. Compounding with Hazadrous and/or Potent Pharmaceuticals, International Academy of Compounding Pharmacists.
• 125.Milunsky A., Graef J.W., Gaynor M.F. Jr. (1968) Methotrexate-induced congenital malformations. With a review of the literature. J. Pediatr. 72, 790- 795.
• 126.Molin L., Larse T.E. (1972) Psoriasis, methotrexate, and cancer. Arch. Dermatol. 105, 292.
• 127.Muller S.A., Farrow G.M., Martalock D.L. (1969) Cirrhosis caused by methotrexate in the treatment of psoriasis. Arch. Dermatol. 100, 523–530.
• 128.Naumann B.D. Sargent E.V., Starkman B.S., Fraser W.J., Becker G.T., Kirk G.D. (1996) Performancebased exposure control limits for pharmaceutical active ingredients. Am. Ind. Hyg. Assoc. J. 57(1), 33–42.
• 129.Newbold P.C.H., Stoughton R.B. (1972) Percutaneous absorption of methotrexate. J. Invest. Dermatol. 58, 319–322.
• 130.Nguyen C., Duhl A.J., Escallon C.S., Blakemore K.J. (2002) Multiple anomalies in a fetus exposed to low-dose methotrexate in the first trimester. Obstet. Gynecol. 99(4), 599–602.
• 131.NIOSH Alert (2004) Preventing occupational exposures to antineoplastics and other hazardous drugs in health care settings. Department of health and human services. Center for disease control and prevention NIOSH. Cincinnati, OH 45226–1998. Publication Number 2004−165. September 2004 [NIOSH Web site at www.cdc.gov/niosh].
• 132.NIOSH List of Antineoplastic and other hazardous drugs in healthcare settings (2012). Departament of health and human services. Center for Disease Control and Prevention National Institute for Occupational Safety and Health.
• 133.NTP, Chemical repository methotrexate (1991) Radian Corporation, August 29.
• 134.Ohbayashi M., Suzuki M., Yashiro Y., Fukuwaka S., Yasuda M., Kohyama N., Kobayashi Y., Yamamoto T. (2010) Induction of pulmonary fibrosis by methotrexate treatment in mice lung in vivo and in vitro. J. Toxicol. Sci. 35 (5), 653–661.
• 135.OSHA (1988) Methotrexate [https://www.osha.gov/dts/sltc/methods/partial/pv2146/pv2146] (pdf).
• 136.OSHA(2006) (Occupational Safety and Health Administreation). United States Department of Labour. Methotrexate Health Factors. [https://www.osha.gov/dts/chemicalsampling/data/CH_250840.html].
• 137.Padmanabhan S., Tripathi D.N., Vikram A., Ramarao P., Jena G.B. (2008) Cytotoxic and genotoxic effects of methotrexate in germ cells of male Swiss mice. Mutat. Res. 655(1–2), 59–67.
• 138.Penn L., Starzl T.E. (1973) The effect of immunosuppression on cancer [W:] Proceedings of the 7th National Cancer Conference. Philadelphia, Lippincott 943–947.
• 139.Pethran A., Schierl R., Hauff K., Grimm C.-H., Boos K.-S., Nowak D. (2003) Uptake of anti-neoplastic agents in pharmacy and hospital personnel. Part 1. Monitoring of urinary concentrations. Int. Arch. Occup. Environ. Health 76, 5–10.
• 140.Pfizer (2012) Material safety data sheet methotrexate. United Kongdom Ver. 2.0 13.03.2012 [http://www.pfizer.com/sites/default/files/products/material_safety_data/PZ00130] pdf.
• 141.Pfizer (2011) Product monograph. Methotrexate. Pfizer, Canada Inc. Quebec.
• 142.Polovich M., Gieseker E. (2011) Occupational hazardous drug exposure among non-oncology nurses. Medsurg. Nursing 20(2), 79–86.
• 143.Powell H.R., Ekert H. (1971) Methotrexate-induced congenital malformations. Med. J. Aust. 2, 1076– 1077.
• 144.Propping P., Röhrbor G., Buselmaier W. (1972) Comparative investigations on the chemical induction of point mutations and dominant lethal mutations in mice. Mol. Gen. Genet. 117, 197–209.
• 145.Pucci E., Matozzo F., Luppi P., Micoli G., Sottani C., Minoia C., Sandrini G., Nappi G. (2005) La Cefalea sintomo „sentinella” nel personale addetto alla preparazione e somministrazione di chemioterapici antiblastici [Headache as “sentinel” symptom in personnel involved in the preparation and administration of antineoplastic drugs.]. G. Ital. Med. Lav. Ergon. 27(4) 412–416.
• 146.Robinson J.W.L., Antonioli J.-A., Vannotti A. (1966) The effect of oral methotrexate on the rat intestine. Biochem. Pharmacol. 15, 1479–1489.
• 147.Rees R.B., Bennett J.H., Maibach H.L., Arnold H.L. (1967) Methotrexate for psoriasis. Arch. Dermatol. 95, 2–11.
• 148.Regelson W., Bross L.0., Hananian J., Nigogosya G. (1965) Incidence of second primary tu mors in children with cancer and leukemia. A seven-year survey of 150 consecutive autopsied cases. Cancer 18, 58–72.
• 149.Ringrose C.A.D. (1974) Carcinoma in situ of the cervix after amethopterin therapy. Am. J. Obstet. Gynecol. 119, 1132–1133.
• 150.Roenigk H.H., Jr. Bergfeld W.F., St Jacques R., Owens F.J., Hawk W.A. (1971) Hepatotoxicity of methotrexate in the treatment of psoriasis. Arch. Derratol. 103, 250–261.
• 151.Rombaldi F., Cassini C., Salvador M., Saffi J., Erdtmann B. (2009) Occupational risk assessment of genotoxicity and oxidative stress in workers handling anti-neoplastic drugs during a working week. Mutagenesis 24(2), 143–148.
• 152.Roschlau G., Justus J. (1971) Carcinogenic action of methotrexate and cyclophosphamide in animal experiments (Ger.) Dtsch. Gesundheitswes. 26, 219–222.
• 153.Ross G.T. (1976) Congenital anomalies among children born to mothers receiving chemotherapy for gestational trophoblastic neoplasm. Cancer 37, 1043–1047.
• 154.RTECS, Registry of Toxic Effects of Chemical Substances (2010).
• 155.Rubino F.M., Florida L., Pietropaolo A.M., Tavazzani M., Colombi A. (1999) Measurement of surface contamination by certain antineoplastic drugs using high-performance liquid chromatography. Applications in occupational hygiene investigations in hospital environment. Med. Lav. 90(4), 572–583.
• 156.Rustia M., Shubik P. (1973) Life-span carcinogenicity tests with 4-amino-N10-methylpteroylglutamic acid (methotrexate) in Swiss mice and Syrian golden hamsters. Toxicol. Appl. Pharmacol. 26, 329–338.
• 157.Rustin G.J., Booth M., Dent J., Salt S., Rustin F., Bagshawe K.D. (1984) Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours. Br. Med. J. (Clin Res Ed) 288(6411), 103– 106.
• 158.Ruymann F.B., Mosijczuk A.D., Sayers R.J. (1977) Hepatoma in a child with methotrexate-induced hepatic fibrosis. J. Am. Med. Assoc. 238, 2631–2633.
• 159.Sabatini L., Barbieri A., Lodi V., Violante F.S. (2012) Biological monitoring of occupational exposure to antineoplastic drugs in hospital settings. Med. Lav. 103(5), 394–401.
• 160.Saigal S., Singh R.K., Poddae B. (2012) Acute methotrexate toxicity presenting as multiorgan failure and acute pneumonitis. A rare case report. Ind. J. Crittical. Care Medicine 16(4) 225–227.
• 161.Salliot C., van der Heijde D. (2009) Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis. A systematic literature research. Ann. Rheum Dis. 68, 1100–1104.
• 162.Santa Cruz Biotechnology, Inc. Safety Data Sheet [http://datasheets.scbt.com/sc-3507] (pdf).
• 163.Scherf H.R., Schmähl D. (1975) Experimental investigations on immunodepressive properties of carcinogenic substances in male Sprague-Dawley rats. Recent Results Cancer Res. 52, 76–87.
• 164.Selevan S.G., Lindbohm M.L., Hornung R.W., Hemminki K. (1985) A study of occupational exposure to antineoplastic drugs and fetal loss in nurses. N. Engl. J. Med. 313, 1173–1178.
• 165.Schmähl D., Habs M. (1976) Life-span investigations for carcinogenicity of some immune-stimulating, immunodepressive and neurotropic substances in Sprague-Dawley rats. Z. Krebsforsch. 86, 77–84.
• 166.Schmahl D., Osswald H. (1970) Experimental studies on carcinogenic effects of anticancer chemotherapeutics and immu nosuppressives (Ger.). Arzneimittel-Forsch./Drug Res. 20, 1461–1467.
• 167.Schröter R., Kelleter R., Kuhn D. (1971) Reticulosis as a long-term side-effect of methotrexate therapy in a patient with generalized psoriasis and psoriatic arthritis. Dermatologica 143, 131–136.
• 168.Schöning FW. (1967) Teratospermie nach Verabreichung von Methotrexat. (Teratospermia after administration of methotrexate). Z Haut Geschlechtskr 42(8), 271–275.
• 169.Scott W.J., Wilson J.G., Ritter E.J., Fradkin R. (1978) Furtherstudiesondistributionofteratogenic drugs in pregnant rats and rhesus monkeys. [W:] Role of pharmacokinetics in prenatal and perinatal toxicology. [Red.] O. Neubert, H.-J. Merker, H. Nau, J. Langman. Stuttgart, Georg Thieme 499– 505.
• 170.Seino Y., Nagao M., Yahag T., Hoshi A., Kawachi T., Sugimura T. (1978) Mutagenicity of several classes of antitumor agents to Salmonella typhimurium T A98, TA 100, and T A92. Cancer Res. 38, 2148–2156.
• 171.Sessink P., Anzion R.B., van der Broek P., Bos R.P. (1992) Detection of contamination with antineoplastic agents in a hospital pharmacy department. Pharmaceutisch Weekbland Scientific ed. 14(1) 16– 22.
• 172.Sessink P.J.M., Friemel N.S.S., Anzion R.B.M., Bos R.P. (1994) Biological and environmental monitoring of occupational exposure of pharmaceutical plant workers to methotrexate. Int. Arch. Occup. Environ. Health 65, 401–403.
• 173.Sessink P.J.M., Wittenhorst B.C.J., Anzion R.B.M., Bos R.P. (1997) Exposure of pharmacy technicians to antineoplastic agents. Reevaluation after additional protective measures. Arch. Environ. Health 52(3) 240–245.
• 174.Shaik M.S., Haynes A., McSween J., Ikediobi O., Kanikkannan N., Singh M. (2002) Inhalation delivery of anticancer agents via HFA-based metered dose inhaler using methotrexate as a model drug. J. Aerosol. Med. Fall 15(3), 261–70.
• 175.Shahin A.A., Ismail M., Saleh A.M., Moustafa H.A., Aboul-Ella A.A., Gabr H.M. (2001) Protective effect of folinic acid on low-dose methotrexate genotoxicity. Z Rheumatol. 60(2), 63–8.
• 176.Shamberger R.C., Rosenberg S.A., Seipp C.A., Sherins R.J. (1981) Effects of high-dose methotrexate and vincristine on ovarian and testicular functions in patients undergoing postoperative adjuvant treatment of osteosarcoma. Cancer Treat. Rep. 65, 739–746.
• 177.Shehata W.M., Meyer R.L. (1980) The enhancement effect of irradiation by methotrexate. Report of three complications. Cancer 46, 1349–1352.
• 178.Skalko R.G., Gold M.P. (1974) Teratogenicity of methotrexate in mice. Teratology 9, 159 The Hague 164.
• 179.Skov T., Maarup B., Olsen J., Rorth M., Winthereik H., Lynge E. (1992) Leukaemia and reproductive outcome among nurses handling antineoplastic drugs. Brit. J. Ind. Med. 49 855 The Hague 861.
• 180.Smeland E., Bremnes R.M., Andersen A., Jaeger R., Eide T.J., Huseby N.E., Aarbakke J. (1994) Renal and hepatic toxicity after high-dose 7-hydroxymethotrexate in the rat. Cancer. Chemother Pharmacol 34, 119.
• 181.Smeland E., FuskevaÊg O.M., Nymann K., Svendsen J.S., Olsen R., Lindal S., Bremnes R.M., Aarbakke J. (1996) High-dose 7-hydromethotrexate. Acute toxicity and lethality in a rat model. Cancer Chemother Pharmacol 37, 415–422.
• 182.Stefanowicz J., Rückemann-Dziurdzińska K., Owczuk R., Maciejka-Kapuścińska L., Balcerska A. (2011) Co wiemy o nefrotoksyczności metotreksatu u dzieci? Forum Nefrologiczne 4(1), 20–25.
• 183.Stewart W.D., Wallace S.M., Runikis J.O. (1972) Absorption and local action of methotrexate in human and mouse skwsp. Arch. Dermatol. 106, 357– 361.
• 184.Strum W.B., Liem H.H. (1977) Hepatic uptake, intracellular protein binding and biliary excretion of amethopterwsp. Biochem. Pharmacol. 26, 1235– 1240.
• 185.Stuart J.F.B., Calman K.C., Watters J., Paxton J., Whiting B., Lawrence J.R., Steele W.H., McVie J.G. (1979) Bioavailabilityof methotrexate: implications for clinicat use. Cancer Chemother. Pharmacoi. 3, 239–241.
• 186.Summary of internal OEL for cytotoxic drugs (2012) [W:] Safety and health handbook for cytotoxic drugs. Murff SJ. Government Institutes 2012.
• 187.Sutton L., Swinehart J.W., Allen C., Kaplan A.S. (2001) A clinical study to determine the efficacy and safety of 1% methotrexate/Azone (MAZ) gel applied topically once daily with patients with psoriasis vulgaris. Int. J. Dermatol. 40, 464–7.
• 188.Świerkot J., Sokolik R., Gruszecka-Marczyńska K., Międzybrodzki R., Szechiński J. (2008) Skuteczność leczenia i występowanie działań niepożądanych w trakcie terapii metotreksatem podawanym doustnie i podskornie chorym na reumatoidalne zapalenie stawow. Reumatologia 46(6), 322–329.
• 189.Tavassoli F.A., Lynch R.G. (1974) Occult adenocarcinoma of the pancreas in a 17-year-old patient with immunosuppressed leukemia. Gastroenterologym 66, 1054–1057
• 190.The Merck Index (1976) [Red.] M. Windholz. 9th ed., Rahway, NJ, Merck & Co. 782.
• 191.Trier J.S. (1961) Morphologic changes in human small intestinal mucosa induced by methotrexate (abstract 282). Proc. Am. Assoc. Cancer Res. 3, 273.
• 192.Turci R., Sottani C., Ronchi A., Minoia C. (2002) Biological monitoring of hospital personel occupationally exposed to antineoplastic agents. Toxicol. Letters 134 57–64.
• 193.U.S. Pharmacopeia. Safety Data Sheet [http://www.usp.org/pdf/EN/referenceStandards/msds/1414003.pdf].
• 194.U.S. EPA, Estimation Programs Interface (EPI), ver. 3.11. U.S. EPA version for Windows. Washington, DC: U.S. EPA (2003). Available from, as of Dec. 15, 2004 [http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm].
• 195.Valanis B.G., Vollmer W.M., Labuhn K.T., Glass A.G. (1993) Association of antineoplastic drug handling with acute adverse effects in pharmacy personnel. American Journal of Health-System Pharmacy March 1, 50(3) 455–462.
• 196.Valanis B.G., Vollmer W.M., Labuhn K.T., Glass A.G. (1993b) Acute symptoms associated with antineoplastic druh handling among nurses. Cancer Nursing 16(4) 288–295.
• 197.Valanis B., Vollmer W., Labuhn K., Glass A. (1997) Occupational exposure to antineoplastic agents and self-reported infertility among nurses and pharmacists. J. Occup. Environ. Med. 39(6), 574–580.
• 198.Vogl S.E. (1978) Acute leukemia complicating treatment of glioblastoma multiforme. Cancer 41, 333–336.
• 199.van Scott E.J., Reinertson R.P. (1959) Morphologic and physiologic effects of chemotherapeutic agents in psoriasis. J. Invest. Dermatol. 33, 357–369.
• 200.van Swelm R., Laarakkers C., Kooijmans-Otero M., de Jong E., Masereeuw R., Russel F. (2013) Biomarkers for methotrexate-induced liver injury. Urinary protein profiling of psoriasis patients. Toxicol. Letters 221 219–224.
• 201.van Thiel D.H., Ross G.T., Lipsett M.B. (1970) Pregnancies after chemotherapy of trophoblastic neoplasms. Science 169, 1326–1327.
• 202.Vega A., Cabanas R., Contreras J. (1994) Anaphylaxis to methotrexate. A possible IgE-mediated mechanism. J. Allergy Clwsp. Immunol. 94, 268– 70.
• 203.Voorhees J.J., Janzen M.K., Harrell E.R., Chakrabarti S.G. (1969) Cytogenetic evaluation of methotrexate-treated psoriatic patients. Arch. Dermatol. 100, 269–274.
• 204.Walden P.A.M., Bagshawe K.O. (1976) Reproductive performance of women successfully treated for gestational trophoblastic tumors. Am. J. Obstet. Gynecol. 125, 1108–1114.
• 205.Walusiak-Skorupa J., Wagrowska-Koski E., Pałczyński C. (2003) Ocena skutkow zdrowotnych zawodowej ekspozycji na cytostatyki u personelu medycznego w świetle obowiązującej profilaktyki. Badanie przekrojowe. Medycyna Pracy 53(3) 229– 236.
• 206.Walusiak-Skorupa J., Wagrowska-Koski E., Pałczyński C. (2009) Cytostatyki. Narażenie zawodowe. Skutki zdrowotne. Profilaktyka. Orzecznictwo. Łodź, IMP wyd. III.
• 207.Walusiak-Skorupa J., Wągrowska-Koski E. (2008) Zasady postępowania przy stosowaniu lekow cytostatycznych. Praca i Zdrowie 3, 38–40.
• 208.Weisburger E.K. (1977) Bioassay program for carinogenic hazards of cancer chemotherapeutic agents. Cancer 40, 1935–1949.
• 209.Wick C., Slawson M.H., Jorgenson J.A., Tyler L.S. (2003) Using a closed-system protective device to reduce personnel exposure to antineoplastic agents. Am. J. Health Syst. Pharm. 60, 2314–2320.
• 210.Wilson J.G. (1971) Use of rhesus monkeys in teratological studies. Fed. Proc. 30, 104–109.
• 211.Wilson J.G. (1974) Teratologie causation in man and its evaluation in non-human primates. Excerpta Medica Int. Congr. Ser. 310, 191.
• 212.Wilson J.G., Scott W.J., Ritter E.J., Fradkin R. (1979) Comparative distribution and embryotoxicity of methotrexate in pregnant rats and rhesus monkeys. Teratology 19, 71–80.
• 213.Wong L.S., Tymms K.E., Buckley N.A. (2009) Potential for methotrexate exposure through contamination during parenteral use as an immunosupresant. Int. Med. J. 39, 379–383.
• 214.Woolas R.P., Bower M., Newlands E.S., Seckl M., Short D., Holden L. (1998) Influence of chemotherapy for gestational trophoblastic disease on subsequent pregnancy outcome. Br. J. Obstet. Gynaecol. 105(9), 1032–1035.
• 215.Zaharko O.S., Dedrick R.L., Young D.M., Peale A.L. (1976) Tolerance of long-term methotrexate infusions by mice. Biochem. Pharmacol. 25, 1317– 1321.
• 216.Ziegler E., Mason H.J., Baxter P.J. (2002) Occupational exposure to cytotoxic drugs in two UK oncology wards. Occup. Environ. Med. 59, 608–612.