Cyklofosfamid : dokumentacja proponowanych dopuszczalnych wielkości narażenia zawodowego

• Autorzy: Gromiec J.

Warianty tytułu

EN

Cyclophosphamide : documentation of proposed values occupational exposure limits (OELs)

• Języki publikacji: PL

Abstrakty

PL

Cyklofosfamid ma postać białego, drobnego, bezwonnego proszku (monohydrat), który pozbawiony wody krystalizacyjnej ma postać oleistej, półpłynnej substancji ciemniejącej pod wpływem światła. Cyklofosfamid działa cytostatycznie i immunosupresyjnie. Stosowany jest w leczeniu: ziarnicy złośliwej, chłoniaków złośliwych, szpiczaka mnogiego, przewlekłej białaczki limfatycznej, raka jajnika, nieoperacyjnego raka sutka oraz nabłoniaka oskrzeli. Jako środek immunosupresyjny cyklofosfamid jest stosowany w leczeniu: zespołu nerczycowego, liszaja rumieniowatego, reumatoidalnego zapalenia stawów, niedokrwistości immunohemolitycznych oraz podczas transplantacji nerek i szpiku. Lek podaje się doustnie w postaci tabletek lub drażetek oraz pozajelitowo po rozpuszczeniu substancji ex tempore w wodzie do wstrzykiwań. Stosuje się go również do perfuzji narządów, w których rozwija się nowotwór. Stosowany jest zarówno pojedynczo, jak i (najczęściej) w połączeniu z innymi lekami przeciwnowotworowymi. Podczas produkcji cyklofosfamidu głównymi drogami narażenia zawodowego są układ oddechowy i skóra. Skóra jest główną drogą narażenia personelu medycznego na cyklofosfamid, dlatego większość danych o poziomach narażenia w szpitalach dotyczy stężeń związku na powierzchni stołów, na których są przygotowywane preparaty dla pacjentów, a także obserwowanych stężeń cyklofosfamidu na skórze i w moczu personelu. Brak jest danych na temat zawodowego narażenia podczas produkcji cyklofosfamidu w Polsce. Nie ma informacji o tym, że cyklofosfamid jest w Polsce produkowany. Zgodnie z danymi, nadesłanymi przez zakłady pracy do Centralnego Rejestru Danych o Narażeniu na Substancje Chemiczne, ich Mieszaniny, Czynniki lub Procesy technologiczne o Działaniu Rakotwórczym w Łodzi, na cyklofosfamid było narażonych zawodowo w Polsce 1476 osób w 2001 r. Według raportu Krajowego Konsultanta w dziedzinie pielęgniarstwa onkologicznego w 2010 r. (dane niepełne, obejmujące jedynie 12 województw) liczba pielęgniarek w placówkach onkologicznych wynosiła łącznie 5077. Wartość LD50 po podaniu per os cyklofosfamidu szczurom wynosi 180 mg/kg mc., a w przypadku myszy 137 mg/kg mc. Leukopenia była głównym skutkiem działania cyklofosfamidu na układ krwiotwórczy u: myszy, szczurów i psów. Stwierdzono również zahamowanie czynności szpiku kostnego i spadek liczby płytek krwi. Związek u: myszy, szczurów i psów, powodował: martwicę pęcherza oraz nabłonka kanalików i miedniczek nerkowych, a umiarkowane uszkodzenia obserwowano również w wątrobie. Dane dotyczące działania toksycznego cyklofosfamidu na ludzi pochodzą od pacjentów leczonych tym związkiem. Cyklofosfamid u ludzi w warunkach narażenia ostrego powodował: uszkodzenie szpiku kostnego, krwotoczne zapalenie pęcherza, a także kardiomiopatię. Kardiotoksyczność wywoływana przez cyklofosfamid objawia się w szerokim zakresie – od małych zmian w ciśnieniu krwi, przez zmiany w EKG i niemiarowość do wtórnej kardiomiopatii ze zmniejszoną frakcją wyrzutową lewej komory (LVEF) i niewydolnością serca, zakończoną śmiercią, w bardzo rzadkich przypadkach. Najczęstszym skutkiem ubocznym terapii cyklofosfamidem chorób autoimmunologicznych (np. układowego tocznia rumieniowatego, artretyzmu reumatoidalnego, ziarniniaka Wegenera, chłoniaków nieziarniczych) jest działanie toksyczne na pęcherz moczowy. Zapadalność pacjentów na krwotoczne zapalenie pęcherza jest rzędu 12 ÷ 41% i skutek ten występował u pacjentów, którzy otrzymywali ponad 100 g leku doustnie w ciągu ponad 30 miesięcy. Za toksyczne działanie cyklofosfamidu na pęcherz jest odpowiedzialna akroleina, będąca jego metabolitem, natomiast przy dożylnym podawaniu leku zapalenie pęcherza jest niezwykle rzadkie. Innymi objawami stwierdzanymi u pacjentów otrzymujących cyklofosfamid były: retencja sodu i wody, zwłóknienie płuc, zaburzenia widzenia, pigmentacja paznokci, jednakże jego rola w tych przypadkach nie została wyjaśniona. Genotoksyczność cyklofosfamidu potwierdzono w wielu badaniach, prowadzonych w warunkach in vivo oraz in vitro na hodowlanych modelach zwierzęcych. Przeprowadzono znaczną liczbę badań właściwości cytogenetycznych cyklofosfamidu na: traszkach, gryzoniach, psach i naczelnych, uzyskując niezmiennie dodatnie wyniki. W wielu doniesieniach opisano tworzenie adduktów DNA u ludzi pod wpływem działania cyklofosfamidu. Międzynarodowa Agencja Badań nad Rakiem (IARC) uznała, że są wystarczające dowody na działanie rakotwórcze cyklofosfamidu na ludzi. Cyklofosfamid wywołuje u ludzi raka pęcherza i ostrą białaczkę szpikową. Uznano również, że są wystarczające dowody działania rakotwórczego tego związku na zwierzęta doświadczalne i sklasyfikowano cyklofosfamid jako Cyklofosfamid. Dokumentacja proponowanych dopuszczalnych wielkości narażenia zawodowego związek rakotwórczy dla ludzi (Grupa 1.). W Unii Europejskiej cyklofosfamid został zaklasyfikowany jako substancja rakotwórcza kategorii 1.A i mutagenna kategorii 2.B. Cyklofosfamid wpływa na rozrodczość u ludzi zarówno w okresie leczenia, jak i przez krótki czas po jego zakończeniu. Związek ten powoduje u ludzi zaburzenia płodności i zaburzenia miesiączkowania. Cyklofosfamid jest teratogenny dla wielu gatunków zwierząt, m.in. dla: szczurów, myszy, królików i naczelnych. Jest odpowiedzialny za: zniekształcenia i deformacje w układzie kostnym, tkankach miękkich oraz zwiększoną liczbę resorpcji, a rodzaj i częstość deformacji są ściśle zależne od czasu i wielkości dawki. Cyklofosfamid działa szkodliwe na zarodki i prowadzi do poronień. Narażenie na cyklofosfamid w pierwszym trymestrze ciąży może powodować takie liczne wady rozwojowe płodu, jak: uszkodzenia kośćca i podniebienia oraz zniekształcenia kończyn. Cyklofosfamid wchłania się: drogą inhalacyjną, z przewodu pokarmowego, z jamy otrzewnej i przez skórę. W przypadku narażenia zawodowego personelu medycznego skóra uważana jest za główną drogę wchłaniania. Zarówno w Polsce, jak i w innych państwach nie ustalono dotychczas wartości najwyższego dopuszczalnego stężenia (NDS) cyklofosfamidu w powietrzu na stanowiskach pracy ani wartości dopuszczalnego stężenia w materiale biologicznym (DSB) dla narażenia zawodowego. Za podstawę do wyprowadzenia wartości NDS przyjęto działanie rakotwórcze cyklofosfamidu na zwierzęta. Wykorzystano współczynnik nachylenia krzywej dawka-odpowiedź na poziomie 0,57 mg/kg mc./dzień dla nowotworów pęcherza obliczony na podstawie wyników całożyciowego narażenia szczurów na cyklofosfamid drogą pokarmową. Średnia dawka całożyciowa dla ryzyka 10-4 wynosi 1,754 - 10-4 mg/kg mc./dzień, co w warunkach narażenia zawodowego odpowiada stężeniu w powietrzu 0,01 mg/m3 i taką wartość postanowiono zaproponować jako wartość NDS. Wartość NDS cyklofosfamidu w obliczonej wysokości powinna chronić pracowników również przed białaczką i działaniem na rozrodczość. Zaproponowano również przyjęcie wartości dopuszczalnego stężenia w materiale biologicznym (DSB) w wysokości 1 μg cyklofosfamidu w całodobowej zbiórce moczu. Brak jest podstaw merytorycznych do ustalenia wartości najwyższego dopuszczalnego stężenia chwilowego (NDSCh). Zaproponowano dla cyklofosfamidu zastosowanie następującego oznakowania: Carc. 1A – substancja rakotwórcza kategorii 1.A, „skóra” – wchłanianie substancji przez skórę może być podobnie istotne, jak przy narażeniu drogą oddechową oraz oznakowanie literami „Ft” – substancja działająca szkodliwie na płód.

EN

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 immunosuppressant 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, Mixtures 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 cyclophosphamide 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 cyclophosphamide is caused by the formation of acrolein, which is its metabolite; hemorrhagic cystitis is, however, extremely rare following intravenous administration. Another symptoms in cyclophosphamide-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 cyclophosphamide 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 musculoskeletal 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 cyclophosphamide 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 workplace 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 establishing short-term exposure limit (STEL).

Słowa kluczowe

PL

cyklofosfamid; narażenie zawodowe; lek cytostatyczny; substancja rakotwórcza; NDS

EN

cyclophosphamide; occupational exposure; antineoplastic drugs; cancerogenic substances; OEL

• Wydawca: Centralny Instytut Ochrony Pracy - Państwowy Instytut Badawczy
• Czasopismo: Podstawy i Metody Oceny Środowiska Pracy
• Rocznik: 2015
• Tom: Nr 1 (83)
• Strony: 17--71
• Opis fizyczny: Bibliogr. 323 poz., rys., tab.

Twórcy

autor

Gromiec J.

• Instytut Medycyny Pracy im. prof. dr. med. Jerzego Nofera 91-348 Łódź ul. św. Teresy od Dzieciątka Jezus 8

Bibliografia

• 1.Adamiak-Ziemba J., Wnuk M. (1994) Substancje rakotwórcze w środowisku pracy. Zagrożenia zdrowotne w warunkach narażenia zawodowego pracowników służby zdrowia na cytostatyki. Łodź, IMP, t. XI, 66.
• 2.Alarcon R.A. (1976) Studies on the in vivo formation of acrolein: 3-hydroxypropylmercapturic acid as an index of cyclophosphamide (NSC- 26271) activation. Cancer Treat. Rep. 60, 327–335.
• 3.Amato D., Niblett J.S. (1977) Neutropenia from cyclophosphamide in breast milk. Med. J. Aust. 1, 383–384.
• 4.American Academy of Pediatrics, Committee on Drugs (2001) The transfer of drugs and other chemicals into human breast milk. Pediatrics 108, 776–89.
• 5.Aptekar R.G., Atkinson J.P., Decker J.L., Wolff S.M., Chu E.W. (1973) Bladder toxicity with chronic oral cyclophosphamide therapy in nonmalignant disease. Arthritis Rheum. 16, 461–7.
• 6.Arnold H., Bourseaux F. (1958) Synthese und Abbau cytostatisch wirksamer cyclischer. N- Phosphamidester des Bis-β(chloraethy1)amins. Angew. Chern. 70, 539–544 [cyt. za IARC 1975].
• 7.Ataya K., Moghissi K. (1989) Chemotherapy induced premature ovarian failure: mechanisms and prevention. Steroids 54, 607–26.
• 8.Austin H.A. III, Klippel J.H., Balow J.E., le Riche N.G., Steinberg A.D., Plotz P.H. i wsp. (1986) Therapy of lupus nephritis: controlled trial of prednisone and cytotoxic drugs. N. Engl. J. Med. 314, 614–9.
• 9.Bagley C.M. Jr., Bostick F.W., DeVita V.T. J. (1973) Clinical pharmacology of cyclophosphamide. Cancer Res. 33, 226–233.
• 10.Baker G.L., Kahl L.E., Zee B.C., Stolzer B.L., Agarwal A.K., Medsger T.A. Jr. (1987) Malignancy following treatment of rheumatoid arthritis with cyclophosphamide. Long-term case-control follow-up study. Am. J. Med. 83, 1–9.
• 11.Balu N., Gamcsik M.P., Colvin M.E., Colvin O.M., Dolan M.E., Ludeman S.M. (2002) Modified guanines representing O6-alkylation by the cyclophosphamide metabolites acrolein and chloroacetaldehyde:synthesis, stability, and ab initio studies. Chem. Res. Toxicol. 15, 380–387 [cyt. za IARC 2011].
• 12.Bashour B.N., Mancer K., Rance C.P. (1973) Malignant mixed Mullerian tumor of the cervix following cyclophosphamide therapy for nephrotic syndrome. J. Pediatr. 82, 292–293.
• 13.Baxter (2009) Charakterystyka produktu leczniczego: endoxan. Baxter Polska Sp. z o.o. [http://baxter.com.pl/downloads/charakterystyki/Oncology/Endoxan_50mg.pdf].
• 14.Bennett A.H. (1974) Cyclophosphamide and hemorrhagic cystitis. J. Urol. 111, 603–606.
• 15.Bergsagel D.E., Robertson G.L., Hasselback R. (1968) Effect of cyclophosphamide on advanced lung cancer and the hematological toxicity of large, intermittent intravenous doses. Canad. Med. Ass. J. 98, 532–538.
• 16.Black S.M., Ellard S., Meehan R.R., Parry J.M., Adesnik M., Beggs J.D., Wolf C.R. (1989) The expression of cytochrome P450IIB1 in Saccharomyces cerevisiae results in an increased mutation frequency when exposed to cyclophosphamide. Carcinogenesis 10, 2139–2143 [cyt. za IARC 2011].
• 17.Blatt J., Mulvihill J.J., Ziegler J.L., Young R.C., Poplack D.G. (1980) Pregnancy outcome following cancer chemotherapy. Am. J. Med. 69, 828–832.
• 18.Bos P.M.J., Brouwer D.H., Stevenson H., Boogaard P.J., de Kort W.L.A.M., van Hemmen J.J. (1998) Proposal for the assessment of quantitative dermal exposure limits in occupational environments: part I. Development of a cocept to derive a quantitative dermal exposure limit. Occup. Environ. Med. 55, 795–804.
• 19.Branda R.F., Brooks E.M., Chen Z., Naud S.J., Nicklas J.A. (2002) Dietary modulation of mitochondrial DNA deletions and copy number after chemotherapy in rats. Mutat. Res. 501, 29–36.
• 20.Brincker H., Mouridsen H.T., Andersen K.W., Rose C., Dombernowsky P. (1989) Castration induced by cytotoxic chemotherapy (letter). J. Clin. Oncol. 7, 679–80.
• 21.Brinkworth M.H., Nieschlag E. (2000) Association of cyclophosphamideinduced malemediated, foetal abnormalities with reduced paternal germcell apoptosis. Mutat. Res. 447, 149–54.
• 22.Brock N., Gross R., Hohorst H.-J., Klein H.O., Schneider B. (1971) Activation of cyclophosphamide in man and animals. Cancer 27, 1512–1529.
• 23.Brock N., Stekar J., Pohl J., Niemeyer U., Scheffler G. (1979a) Acrolein, the causative factor of urotoxic side-effects of cyclophosphamide, ifosfamide, trofosfamide and sufosfamide. Arzneimittel- Forsch./Drug Res. 29, 659–661 [cyt. za IARC 2011].
• 24.Brock N., Stekar J., Pohl J., Scheef W. (1979b) Antidote against the urotoxic effects of the oxazaphosphorine derivatives cyclophosphamide, ifosfamide and trofosfamide (Ger.). Naturwissenschaften 66, 60–61.
• 25.Burgaz S., Karahalil B., Bayrak P., Taşkin L., Yavuzaslan F. i wsp. (1999) Urinary cyclophosphamide excretion and micronuclei frequencies in peripheral lymphocytes and in exfoliated buccal epithelial cells of nurses handling antineoplastics. Mutat. Res. 439, 97–104.
• 26.Burgaz S., Karahalil B., Canli Z., Terzioglu F., Ancel G., Anzion R.B.M., Bos R.P., Hünttner E. (2002) Assessment of genotoxic damage in nurses occupationally exposed to antineoplastics by the analysis of chromosomal aberrations. Hum. Exp. Toxicol. 21, 129–135.
• 27.Busse D., Busch W., Bohnenstengel F., Eichelbaum M., Fischer P. i wsp. (1997) Dose escalation of cyclophosphamide in patients with breast cancer: consequences for pharmacokinetics and metabolism. J. Clin. Oncol. 15, 1885–1896.
• 28.Cai Y., Wu M.H., Ludeman S.M., Grdina D.J., Dolan M.E. (1999) Role of O6 alkylguanine-DNA alkyltransferase in protecting against cyclophosphamide- induced toxicity and mutagenicity. Cancer Res. 59, 3059–3063 [cyt. za IARC 2011].
• 29.van Calsteren K., Verbesselt R., Beijnen J., Devlieger R., De Catte L., Chai D.C., Van Bree R., Heyns L., de Hoon J., Amant F. (2010) Transplacental transfer of anthracyclines, vinblastine, and 4-hydroxy- cyclophosphamide in a baboon model. Gynecol. Oncol. 119(3), 594–600 [cyt. za IARC 2011].
• 30.Cameron J.S., Chantler C., Ogg C.S., White R.H.R. (1974) Long-term stability of remission in nephritic syndrome after treatment with cyclophosphamide. Br. Med. J.7–11.
• 31.Campobasso O., Berrino F. (1972) Early effects of cycloph osphamide on mouse bladder epithelium. Pathol. Microbiol. 38, 144–157.
• 32.Čáp, J., Mišiková Z. (1975) Chronic myelogenous leukaemia as a possible consequence of immunosuppressive treatment of nephrotic syndrome (Ger.). Monatsschr. Kinderheilkd. 123, 718–720.
• 33.Carette S., Klippel J.H., Decker J.L., Austin H.A., Plotz P.H., Steinberg A.D. i wsp. (1983) Controlled studies of oral immunosuppressive drugs in lupus nephritis: a long-term follow-up. Ann. Intern. Med. 99, 1–8.
• 34.Casciato D.A., Scott J.L. (1979) Acute leukemia following prolonged cytotoxic agent therapy. Medicine 58, 32–47.
• 35.van Casteren N.J., van der Linden G.H., Hakvoort- Cammel F.G., Hhlen K., Dohle G.R., van den Heuvel- Eibrink M.M. (2009) Effect of childhood cancer treatment on fertility markers in adult male longterm survivors. Pediatr. Blood Cancer 52(1), 108– 12.
• 36.Cavallo D., Ursini C.L., Perniconi B., Francesco A.D., Giglio M., Rubino F.M., Marinaccio A., Iavicoli S. (2005) Evaluation of genotoxic effects induced by exposure to antineoplastic drugs in lymphocytes and exfoliated buccal cells of oncology nurses and pharmacy employees. Mutat. Res. 587, 45–51 [cyt. za IARC 2011].
• 37.Cazalis P., Caroit M., Zittoun R., Kahn M.-F., de Séze S. (1976) A particular risk in long-term immunosuppressive treatment: a case of acute myelomonocytic leukaemia after treatment with chlorambucil for severe rheumatoid polyarthritis (Fr.). Rev. Rhum. 43, 431–435.
• 38.CEPA (1992) Expedited cancer potency values and proposed regulatory levels for certain proposition 65 carcinogens. California Environmental Protection Agency. Office of Environmental Hazards Assessment, Reproductive and Cancer Hazard Assessment Section [http://oehha.ca.gov/prop65/pdf/ expcancer.pdf].
• 39.Chandramouli K., Sivaramakrishnan V.M. (1969) Radiation and radiomimetic agents. I. The distribution of P 3 2 -labelled cyclophosphamide in albino rats and in humans. Indian J. Cancer 6, 153–164.
• 40.Chang J., Geary C.G. (1977) Therapy-linked leukaemia. Lancet Jan 8, 1(8002), 97.
• 41.Chasko S.B., Keuhnelian J.G., Gutowski W.T. III., Gray G.F. (1980) Spindle cell cancer of bladder during cyclophosphamide therapy for Wegener's granulomatosis. Am. J. Surg. Pathol. 4, 191–196.
• 42.Chaube S., Kreis W., Uchida K., Murphy M.L. (1968) The teratogenic effects of the recent drugs active in cancer chemotherapy. Adv. Teratol. 3, 181–237.
• 43.Chu W.C., Hon C.Y., Danyluk Q., Chua P., Astrakianakis G. (2011) Pilot assessment of the antineoplastic drug contamination levels in British-Columbian hospitals pre- and post-cleaning. I Oncol. Pharm. Practice 18(1), 46–51.
• 44.Clavert J.M., Brun B., Clavert A., Buck P. (1978) Limb anomalies obtained with cyclophosphamide in rabbit embryos (Fr.). Chir. Pediatr. 19, 205–207.
• 45.Clayson D.B., Cooper E.H. (1969) The immediate response of bladder epithelium to injury by chemical carcinogens. Brit. J. Ural. 41, 710–713.
• 46.Clowse M.E.B., Magder L., Petri M. (2005) Cyclophosphamide for lupus during pregnancy. Lupus 14 (8), 593–7.
• 47.Coates A. (1970) Cyclophosphamide in pregnancy. Aust. NZ J Obstet. Gynaecol. 10, 334.
• 48.Cobau C.D., Sheon R.P., Kirsner A.B. (1973) Immunosuppressive drugs and acute leukemia. Ann. Intern. Med. 79, 131–132.
• 49.Codrington A.M., Hales B.F., Robaire B. (2007) Exposure of male rats to cyclophosphamide alters the chromatin structure and basic proteome in spermatozoa. Hum. Reprod. 22(5), 1431–42.
• 50.Cohen S.M., Garland E.M., St John M., Okamura T., Smith R.A. (1992) Acrolein initiates rat urinary bladder carcinogenesis. Cancer Res. 52, 3577– 3581.
• 51.Colvin M. (1978) A review of the pharmacology and clinical use of cyclophosphamide [W:] Clinical pharmacology of anti-neoplastic drugs. Amsterdam, Elsevier/North-Holland Biomedical Press 245–261 [cyt. za IARC 1981].
• 52.Colvin M., Padgett C.A., Fenselau C. (1973) A biologically active metabolite of cyclophosphamide. Cancer Res. 33, 915–918.
• 53.Connors T.A. (1978) Antitumour drugs with latent activity. Biochimie 60, 979–987.
• 54.Connors T.A. (1979) Alkylating drugs, nitrosourea and dialkyltriazenes [W:] Cancer chemotherapy [Red.] H.M. Pinedo. The EORTC Cancer Chemotherapy Annual. Amsterdam, Excerpta Medica, 25– 55 [cyt. za IARC 1981].
• 55.Connors T.A., Cox P.J., Farmer P.B., Foster A.B., Jarman M. (1974) Some studies of the active intermediates formed in the microsomal metabolism of cyclophosphamide and isophosphamide. Biochem. Pharmacol. 23, 115–129.
• 56.Correa A., Cragan J.D., Kucik J.E., Alverson C.J., Gilboa S.M., Balakrishnan R., Strickland M.J., Duke C.W., O'Leary L.A., Riehle-Colarusso T., Siffel C., Gambrell D., Thompson D., Atkinson M., Chitra J. (2007) Reporting birth defects surveillance data 1968-2003. Birth Defects Res. A Clin. Mol. Teratol. 79(2), 65–186.
• 57.Cox P.J. (1979) Cyclophosphamide cystitis–identification of acrolein as the causative agent. Biochem. Pharmacol. 28, 2045–2049.
• 58.Cox P.J., Abel G. (1979) Cyclophosphamide-induced cystitis: its cause and possible clinical significance. Br. J. Cancer 40, 311 [Abstract].
• 59.Cox P.J., Farmer P.B., Jarman M., Kinas R.W., Stec W.J. (1978) Stereoselectivity in the metabolism of the enantiomers of cyclophosphamide in mice, rats and rabbits. Drug. Metab. Disposition 6, 617–622.
• 60.Crocitto L.E., Simpson J.F., Wilson T.G. (1996) Bladder augmentation in the prevention of cyclophosphamideinduced haemorrhagic cystitis in the rat model. Br. J. Urol. 78, 530–533.
• 61.da Cunha I., Saavedra M.J., Pereira da Silva J.A., Malcata A. (2008) Cyclophosphamide induced amenorrhoea in premenopausal women with systemic lupus erythematosus. Acta Reumatol Port 33(1), 69–76.
• 62.Dale G.A., Smith R.B. (1974) Transitional cell carcinoma of the bladder associated with cyclophosphamide. J. Ural. 112, 603–604.
• 63.Darroudi F., Natarajan A.T. (1993). Metabolic activation of chemicals to mutagenic carcinogens by human hepatoma microsomal extracts in Chinese hamster ovary cells (in vitro). Mutagenesis 8, 11– 15.
• 64.Deshayes P., Renier J.C., Bregeon C., Houdent G. (1971) Incidents and accidents with immunosuppressive therapy for rheumatoid polyarthritis (Fr.). Rev. Rhum. 38, 797–806.
• 65.D'Incalci M., Bolis G., Facchinetti T., Mangioni C., Morasca L., Morazzoni P., Salmona M. (1979) Decreased half life of cyclophosphamide in patients under continual treatment. Eur. J. Cancer 15, 7–10.
• 66.D'Incalci M., Sessa C., Colombo N., de Palo G., Semprini A.E., Pardi G. (1982) Transplacental passage of cyclophosphamide. Cancer Treat. Rep. 66(8), 1681–1682.
• 67.Doehmer J., Seidel A., Oesch F., Glatt H.R. (1990) Genetically engineered V79 Chinese hamster cells metabolically activate the cytostatic drugs cyclophosphamide and ifosfamide. Environ Health Perspect 88, 63–65.
• 68.Doehmer J., Wölfel C., Dogra S., Doehmer C., Seidel A., Platt K.L., Oesch F., Glatt H.R. (1992) Applications of stable V79-derived cell lines expressing rat cytochromes P4501A1, 1A2, and 2B1. Xenobiotica 22, 1093–1099.
• 69.Domeyer B.E., Sladek N.E. (1980) Kinetics of cyclophosphamide biotransformation in vivo. Cancer Res. 40, 174–180.
• 70.Duncan J.H., Colvin O.M., Fenselau C. (1973) Mass spectrometric study of the distribution of cyclophosphamide in humans. Toxicol. Appl. Pharmacol. 24, 317–323.
• 71.Durodola J.I. (1979) Administration of cyclophosphamide during late pregnancy and early lactation: a case report. J. Natl. Med. Assoc. 71, 165.
• 72.Eastin W.C., Mennear J.H., Tennant R.W., Stoll R.E., Branstetter D.G. i wsp. (2001) Tg.AC genetically altered mouse: assay working group overview of available data. Toxicol. Pathol. 29, suppl., 60–80.
• 73.Ellard S., Mohammed Y., Dogra S., Wölfel C., Doehmer J., Parry J.M. (1991) The use of genetically engineered V79 Chinese hamster cultures expressing rat liver CYP1A1, 1A2 and 2B1 cDNAs in micronucleus assays. Mutagenesis 6, 461–470.
• 74.Enns G.M., Roeder E., Chan R.T., Ali-Khan Catts Z., Cox V.A., Golabi M. (1999) Apparent cyclophosphamide (cytoxan) embryopathy: a distinct phenotype? Am. J. Med. Genet. 86, 237–241.
• 75.Faber O.K., Mouridsen H.T., Skovsted L. (1975) The effect of chloramphenicol and sulphaphenazole on the biotransformation of cyclophosphamide in man. Sr. J. Clin. Pharmacol. 2, 281–285.
• 76.Faurschou M., Sorensen I.J., Mellemkjaer L., Loft A.G., Thomsen B.S., Tvede N. i wsp. (2008) Malignancies in Wegener’s granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J. Rheumatol. 35, 100–5.
• 77.Fenselau C. (1976) Review of the metabolism and mode of action of cyclophosphamide. J. Assoc. Off. Anal. Chem. 59, 1028–1036.
• 78.Fenselau C., Kan M.-N.N., Billets S., Colvin M. (1975) Identification of phosphorodiamidic acid mustard as a human metabolite of cyclophosphamide. Cancer Res. 35, 1453–1457.
• 79.Fenselau C., Kan M.-N.N., Rao S.S., Myles A., Friedman O.M., Colvin M. (1977) Identification of aldophosphamide as a metabolite of cyclophosphamide in vitro and in vivo in humans. Cancer Res. 37, 2538–2543.
• 80.Fernandez M., Andrade R., Alarcen G.S. (2006) Cyclophosphamide use and pregnancy in Lupus. Lupus 15(1), 59.
• 81.Forni A.M., Koss L.G., Geller W. (1964) Cytological study of the effect of cyclophosphamide on the epithelium of the urinary bladder in man. Cancer 17, 1348–1355.
• 82.Fosdick W.M., Parsons J.L., Hill D.F. (1969) Longterm cyclophosphamide (CP) therapy in rheumatoid arthritis: a progress report, six years ' experience. Arthritis-Rheum. 12, 663.
• 83.Fransman W., Vermeulen R., Kromhout H. (2005). Dermal exposure to cyclophosphamide in hospitals during preparation, nursing and cleaning activities. Int. Arch. Occup. Environ. Health 78, 403–412.
• 84.Fransman W., Huizer D., Tuerk J., Kromhout H. (2007a) Inhalation and dermal exposure to eight antineoplastic drugs in an industrial laundry facility. Int. Arch. Occup. Environ. Health 80, 396–403.
• 85.Fransman W., Peelen S., Hilhorst S., Roeleveld N., Heederik D., Kromhout H. (2007b) A Pooled Analysis to Study Trends in Exposure to Antineoplastic Drugs Among Nurses. Ann. Occup. Hyg. 51(3), 231–239.
• 86.Fransman W., Kager H., Meijster T., Heederik D., Kromhout H., Portengen L., Blaauboer B.J. (2014) Leukemia from dermal exposure to cyclophosphamide among nurses in the Netherlands. Quantitative Assessment of Risk. Ann. Occup. Hyg. 58(3), 271– 282.
• 87.Friedman H.S., Pegg A.E., Johnson S.P., Loktionova N.A., Dolan M.E. i wsp. (1999). Modulation of cyclophosphamide activity by O6-alkylguanine- DNA alkyltransferase. Cancer Chemother Pharmacol. 43, 80–85 [cyt. za IARC 2011].
• 88.Fritz H., Hess R. (1971) Effects of cyclophosphamide on embryonic development in the rabbit. Agents Actions 2(2), 83–86.
• 89.Gibson J.E., Becker B.A. (1968) The teratogenicity of cyclophosphamide in mice. Cancer Res. 28, 475– 480.
• 90.Gibson J.E., Becker B.A. (1971) Effect of Phenobarbital and SKF 525A on placental transfer of cyclophosphamide in mice. J. Pharmacol. expo Ther. 177, 256–262.
• 91.Gilmore L.T., Cowan R.E., Axon A.T.R., Thompson R.P.H. (1979) Controlled trial of cyclophosphamide in active chronic hepatitis. Br. Med. J., 1 (1671), 1120–1121.
• 92.Gismondi C., Dabove L., Dovì M., Picciotto A., Savarino V., Testa R., Mansi C. (1980) Hepatotoxicity of cyclophosphamide in the rat after prolonged treatment: a histomorphological study. Boll. Soc. Ital. Biol. Sper. 56(21), 2166–72 (in Ital.).
• 93.Gorelick N.J., Andrews J.L., deBoer J.G., Young R., Gibson D.P., Walker V.A. (1999) Tissue-specific mutant frequencies and mutational spectra in cyclophosphamide- treated lacI transgenic mice. Environ. Mol. Mutagen. 34, 154–166.
• 94.Green D.M., Kawashima T., Stovall M., Leisenring W., Sklar C.A., Mertens A.C., Donaldson S.S., Byrne J., Robison L.L. (2010) Fertility of male survivors of childhood cancer: a report from the childhood cancer survivor study. J. Clin. Oncol. 28(2), 332–9.
• 95.Greenberg L.H., Tanaka K.R. (1964) Congenital anomalies probably induced by cyclophosphamide. J. Am. Med. Assoc. 188, 423–426.
• 96.Greene M.H., Harris E.L., Gershenson D.M., Malhasian G.D., Melton L., Dempo A.J., Bennet J.M., Moloney W.C., Boice J.D. (1986) Melphalan may be a more potent leukemogen than cyclophosphamide. Ann. Intern. Med. 105, 360–367.
• 97.Haas J.F., Kittelmann B., Mehnert W.H., Staneczek W., Mohner M., Kaldor J.M., Day N.E. (1987) Risk of leukaemia in ovarian tumour and breast cancer patients following treatment by cyclophosphamide. Br. J. Cancer 55, 213–218.
• 98.Habibullah C.M., Chhuttani P.N., Sehgal A.K. (1979) Effect of oral cyclophosphamide on the rat intestine. Indian J. Med. Sci. 33, 180–184.
• 99.Habs M.R., Schmähl D. (1983) Prevention of urinary bladder tumors in cyclophosphamide-treated rats by additional medication with the uroprotectors sodium 2-mercaptoethane sulfonate (mesna) and disodium 2,2A-dithiobis-ethane sulfonate (dimesna). Cancer 51, 606–609.
• 100.Hales B.F., Smith S., Robaire B. (1986) Cyclophosphamide in the seminal fluid of treated males: transmission to females by mating and effect on pregnancy outcome. Tox. Appl. Pharmacol. 84, 423– 430.
• 101.Hartmann A., Herkommer K., Glück M., Speit G. (1995) DNA-damaging effect of cyclophosphamide on human blood cells in vivo and in vitro studied with the single cell gel test (comet assay). Environ. Mol. Mutagen 25, 180–187.
• 102.Hedmer M., Höglund P., Cavallin-Stähl E., Albin M., Jönsson B.A. i wsp. (2008) Validation of urinary excretion of cyclophosphamide as a biomarker of exposure by studying its renal clearance at high and low plasma concentrations in cancer patients. Int. Arch. Occup. Environ. Health 81, 285–293.
• 103.Hegewald G., Barenwald G. (1972) Morphological changes in rat Iiver after long-term cyclophosphamide medication (Ger.). Acta hepatogastroenterol 19, 85–90.
• 104.Hirst M., Mills D.G., Tse S., Levin L., White D.F. (1984) Occupational exposure to cyclophosphamide. Lancet 323 (8370), 186–188.
• 105.Hochberg M.C., Shulman L..E. (1978) Acute leukemia following cyclophosphamide therapy for Sjogren's syndrome. Johns Hopkins Med. J. 142, 211–214.
• 106.Hoorn A.J., Custer L.L., Myhr B.C., Brusick D., Gossen J., Vijg J. (1993) Detection of chemical mutagens using Muta® Mouse: a transgenic mouse model. Mutagenesis 8, 7–10.
• 107.Hoyes K.P., Wadeson P.J., Sharma H.L., Hendry J.H., Morris I.D. (1998) Mutation studies in lacI transgenic mice after exposure to radiation or cyclophosphamide. Mutagenesis 13, 607–612.
• 108.HSDB (2014) [http://toxnet.nlm.nih.gov/cgibin/sis/htmlgen?HSDB].
• 109.IARC (1975) Monographs on the evaluation of carcinogenic risks to humans. T. 9. Some aniziridines, N-,S-, and O-mustards and selenium. Lyon.
• 110.IARC (1987a) Overall evaluations of carcinogenicity: an updating of IARC Monographs volumes 1 to 42. IARC Monographs on the evaluation of carcinogenic risks to humans. T. 7, 1–440.
• 111.IARC (1987b) Genetic and related effects. An updating of selected IARC monographs from volumes 1 to 42. IARC Monographs on the evaluation of carcinogenic risks to humans. Lyon suppl. 6, 1–729.
• 112.IARC (1995) Dry cleaning, some chlorinated solvents and other industrial chemicals. IARC Monographs on the evaluation of carcinogenic risks to humans. T. 63, 1–551.
• 113.IARC (2011) Cyclophosphamide [W:] IARC Monographs on the evaluation of carcinogenic risks to humans. T. 100, A Review of Human Carcinogens. Part A. Pharmaceuticals 65–96.
• 114.IUCLID (2014) Baza danych on-line [http://esis.jrc.ec.europa.eu/].
• 115.IFA (2014) Baza danych GESTIS on-line [http://gestis-en.itrust.de/nxt/gateway.dll?f=templates$ fn=default.htm$vid=gestiseng:sdbeng].
• 116.IUCLID (2011) Chemical Data Sheet.
• 117.Jahnukainen K., Heikkinen R., Henriksson M., Cooper T.G., Puukko-Viertomies L.R., Mkitie O. (2011) Semen quality and fertility in adult longterm survivors of childhood acute lymphoblastic leukemia. Fertil Steril 96(4), 837–42.
• 118.Jaśkiewicz K. (1979) Wywołane cyklofosfamidem uszkodzenia tkanki płucnej u myszy. Ann. Acad. Med. Gedan 9, 71–77.
• 119.Jeffrey L.P. (1987) National Study Commission on Cytotoxic Exposure. Position Statement. The handling of cytotoxic agents by women who are pregnant, attempting to conceive or breast feeding. Jan 12 [http://ctep.cancer.gov/handbook/append_13 .html].
• 120.Joqueviel C., Martino R., Gilard V., Malet-Martino M., Canal P., Niemeyer U. (1998) Urinary excretion of cyclophosphamide in humans, determined by phosphorus-31 nuclear magnetic resonance spectroscopy. Drug. Metab. Dispos. 26, 418–428.
• 121.Johnson W.W., Meadows D.C. (1971) Urinarybladder fibrosis and telangiectasia associated with longterm cyclophosphamide therapy. New Engl. J. Med. 284, 290–294.
• 122.de Junge M.E., Huitema A., Beijnen J.H., Rodenhuis S. (2006) High exposures to bioactivated cyclophosphamide are related to the occurrence of venoocclusive disease of the liver following highdose chemotherapy. Br. J. Cancer 94, 1226–1230.
• 123.Kahn M.F., Arlet J., Bloch-Michel H., Caroit M., Chaouat Y., Renier J.C. (1979) Acute leukaemias after treatment with cytotoxic agents in rheumatology. 19 observations among 2006 patients (Fr.). Nouv. Presse Med. 8, 1393–1397.
• 124.Kalweit S., Utesch D., von der Hude W., Madle S. (1999) Chemically induced micronucleus formation in V79 cells–comparison of three different test approaches. Mutat. Res. 439, 183–190.
• 125.Kanazawa K., Suzuki T., Sakumoto K. (2000) Treatment of malignant ovarian germ cell tumors with preservation of fertility: reproductive performance after persistent remission. Am. J. Clin. Oncol. 23, 244–8.
• 126.Kapadia S.B., Kaplan S.S. (1976) Simultaneous occurrence of non-Hodqkin's lymphoma and acute myelomonocytic leukemia. Cancer 38, 2557–2560.
• 127.Kapadia S.B., Kaplan S.S. (1978) Acute myelogenous leukemia following immunosuppressive therapy for rheumatoid arthritis. Am. J. Clin. Pathol. 70, 301–302.
• 128.Kapadia S.B., Krause J .R., Ellis L.O., Pan S.F., Wald N. (1980) Induced acute non-lymphocytic leukemia following long-term chemotherapy. A study of 20 cases. Cancer 45, 1315–1321.
• 129.Kar A.K., Singh S., Sanyal A.K. (1974) Cyclophosphamide induced hydrocephalus in chick embryos. Indian J. Med. Res. 62, 905–908.
• 130.Kelly W.A., Nelson L.W., Hawkins H.C., Weikel J.H Jr. (1974) An evaluation of the tumorigenicity of cyclophosphamide and urethan in newborn mice. Toxicol. Appl. Pharmacol. 27, 629–640.
• 131.Kende G., Sirkin S.R., Thomas P.R.M., Freeman A.1. (1979) Blurring of vision. A previously undescribed complication of cyclophosphamide therapy. Cancer 44, 69–71.
• 132.Kenney L.B., Laufer M.R., Grant F.D., Grier H., Diller L. (2001) High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer 91, 613–21.
• 133.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.
• 134.Khan M.A., Travis L.B., Lynch C.F., Soini Y., Hruszkewycz A.M., Delgado R.M. i wsp. (1998) P53 mutations in cyclophosphamide-associated bladder cancer. Cancer Epidemiol. Biomarkers Prev. 7, 397–403.
• 135.Kikuno T., Honma M., Ogura S. i wsp. (1995) DNA fingerprint analysis in chemically mutagenized Chinese hamster lung cells. Mutat. Res. 338, 87–93.
• 136.Kirsch-Volders M., Sofuni T., Aardema M., Albertini S., Eastmond D., Fenech M. i wsp. (2003) Report from the in vitro micronucleus assay working group. Mutat. Res. 540, 153–163.
• 137.Kirshon B., Wasserstrum N., Willis R., Herman G.E., McCabe E.R. (1988) Teratogenic effects of first trimester cyclophosphamide therapy. Obstet. Gynecol. 72, 462.
• 138.Knight A., Askling J., Ekbom A. (2002) Cancer incidence in a populationbased cohort of patients with Wegener’s granulomatosis. Int. J. Cancer 100, 82–5.
• 139.Knight A., Askling J., Granath F., Sparen P., Ekbom A. (2004) Urinary bladder cancer in Wegener’s granulomatosis: risks and relation to cyclophosphamide. Ann. Rheum. Dis. 63, 1307–11.
• 140.Köhler E., Merker H. J. (1973) Effect of cyclophosphamide pretreatment of pregnant animals on the activity of nuclear DNA-dependent RNA-polymerases in different parts of rat embryos. Naunyn- Schmiedeberg's Arch. Pharmacol. 277, 71–88.
• 141.Konieczko K., Czerczak S., Kluszczyński D. (2004) Narażenie zawodowe na chemiczne czynniki rakotwórcze w Polsce w 2001 r. Med. Pracy 55(1), 3–6.
• 142.Koss L.G. (1967) A light and electron microscopic study of the effects of a single dose of cyclophosphamide on various organs in the rat. I. The urinary bladder. Lab. Invest. 16, 44–65.
• 143.Koyama H., Wada T., Nishizawa Y., Iwanaga T., Aoki Y., Terasawa T., Kosaki G., Yamamoto T., Wada A. (1977) Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer. Cancer 39, 1403–1409.
• 144.von Kreybig T. (1965) Teratogenic effect of cyclophosphamide during the embryonal development phase in rats (Ger.). Naunyn-Schmiedeberg's Arch. Expo. Pathol. Pharmakol. 252, 173–195.
• 145.Kromhout H., Hoek F., Uitterhoeve R., Huijbers R., Overmars R.F., Anzion R., Vermeulen R. (2000) Postulating a dermal pathway for exposure to antineoplastic drugs among hospital workers. Applying a conceptual model to the three workplace surveys. Ann. Occup. Hyg. 44, 551–560.
• 146.Kugler U., Bauchinger M., Schmid E., Göggelmann W. (1987) The effectiveness of S9 and microsomal mix on activation of cyclophosphamide to induce genotoxicity in human lymphocytes. Mutat. Res. 187, 151–156.
• 147.Kuis W., de Kraker J., Kuijten R.H., Doncker- Wolcke RA., Voute P.A. (1976) Acute lymphoblastic leukaemia after treatment of nephrotic syndrome with immunosuppressive drugs. Helv. Paediatr. Acta 31, 91–95.
• 148.Kulka U., Doehmer J., Glatt H.R., Bauchinger M. (1993) Cytogenetic effects of promutagens in genetically engineered V79 Chinese hamster cells expressing cytochromes P450. Eur. J. Pharmacol. 228, 299–304.
• 149.Kwanyuen P., Erexson G.L., Bryant M.F., Kligerman A.D. (1990) Comparison of sister-chromatid exchange frequencies in mouse T- and B-lymphocytes after exposure to 4-hydroxycyclophosphamide or phosphoramide mustard. Mutat. Res. 245, 293–297.
• 150.Langevitz P., Klein L., Pras M., Many A. (1992) The effect of cyclophosphamide pulses onfertility in patients with lupus nephritis. Am J. Reprod. Immunol. 28, 157–158.
• 151.Lavin P., Koss L.G. (1971) Effects of a single dose of cyclophosphamide on various organs in the rat. III. Electron microscopic study of the liver. Amer. J. Path. 62, 159–168.
• 152.Lazalde B., Grijalva-Flores J., Guerrero-Romero F., Klippel J.H. (2012) Feil syndrome in a boy exposed inadvertently to cyclophosphamide during pregnancy: a case report. Birth Defects Res. A Clin. Mol. Teratol. 94 (4), 249–52.
• 153.Leyder M., Laubach M., Breugelmans M., Keymolen K., De Greve J., Foulon W. (2010) Specific congenital malformationsafter exposure to cyclophosphamide, epirubicin and 5fluorouracil during the first trimester of pregnancy. Gynecol. Obstet. Invest. 71(2), 141–144.
• 154.Liedberg C.F., Rausing A., Langeland P. (1970) Cyclophosphamide hemorrhagic cystitis. Scand. J. Urol. Nephro. 14, 183–190.
• 155.Locher G.W., Cooper E.H. (1970) Repair of rat urinary bladder epithelium following injury by cyclophosphamide. Invest. Urol. 8, 116–123.
• 156.Love R.R., Sowa J.M. (1975) Myelomonocytic leukaemia following cyclophosphamide therapy of rheumatoid disease. Ann. Rheum. Dis. 34, 534– 535.
• 157.Mader R.M., Kokalj A., Kratochvil E., Pilger A., Rüdiger H.W. (2008) Longitudinal biomonitoring of nurses handling antineoplastic drugs. J. Clinical Nursing 18, 263–269.
• 158.Mahgoub N., Taylor B.R., Le Beau M.M., Gratiot M., Carlson K.M. i wsp. (1999) Myeloid malignancies induced by alkylating agents in Nf1 mice. Blood 93, 3617–3623.
• 159.Manny N., Rosenman E., Benbassat J. (1972) Hazard of immunosuppressive therapy. Br. Med. J. 2 (5808), 291.
• 160.Mansi C., Dodero M., Savarino V., Picciotto A., Ciravegna G., Testa R., Celie G. (1979) Toxic effects on mucosa of the oesophagus, stomach and colon and on the pancreas after chronic administration of azathioprine and cyclophosphamide to rats (Ital.). Pathologica 71, 235–241.
• 161.Marazzini F., Macchi L. (1966) Two normal pregnancies in patients receiving cytoxan for Hodgkin`s disease. Ann. Obstet. Ginecol. 88, 825–834.
• 162.Marks J.S., Scholtz C.L. (1977) Sarcoma complicating therapy with cyclophosphamide. Postgrad. Med. J. 53, 48–49.
• 163.Masala A., Faedda R., Alagna S., Satta A., Chiarelli G. i wsp. (1997) Use of testosterone to prevent cyclophosphamideinduced azoospermia. Ann. Intern. Med. 126, 29–25.
• 164.Matějkova E. (1975) The effects of combined administration of cytembena and cyclophosphamide on the blood count and morphology of nucleoli in peripheral-blood lymphocytes in patients with malignant tumors. Neoplasma 22, 45–54.
• 165.McCarroll N., Keshava N., Cimino M., Chu M., Dearfield K. i wsp. (2008) An evaluation of the mode of action framework for mutagenic carcinogens case study. Cyclophosphamide. Environ. Mol. Mutagen. 49, 117–131.
• 166.McCarvill J.T., Lubet R.A., Schechtman L.M., Kouri R.E., Putman D.L. (1990) Morphological transformation of BALB/3T3 cells by various procarcinogens in the presence of a rat liver S-9 activation system. Environ. Mol. Mutagen. 16, 304–310.
• 167.McClain R.M., Keller D., Casciano D., Fu P., Mac- Donald J., Popp J. i wsp. (2001) Neonatal mouse model: review of methods and results. Toxicol. Pathol. 29, 128–137.
• 168.McClure H.M., Wilk A.L., Horigan E.A., Pratt R.M. (1979) Induction of craniofacial malformations in rhesus monkeys (Macaca mulatta) with cyclophosphamide. Cleft` Palate J. 16, 248–256.
• 169.McDiarmid M.A., Iype P.T., Kolodner K., Jacobson- Kram D., Strickland P.T. (1991) Evidence for acrolein-modified DNA in peripheral blood leukocytes of cancer patients treated with cyclophosphamide. Mutat. Res. 248, 93–99.
• 170.McDiarmid M.A., Strickland P.T., Kolodner K., Hansen J., Jacobson-Kram D. (1990) Baseline and phosphoramide mustard-induced sister-chromatid exchanges in cancer patients treated with cyclophosphamide. Mutat. Res. 241, 273–278.
• 171.Meistrich M.L., Wilson G., Brown B.W., da Cunha M.F., Lipshultz L.I. (1992) Impact of cyclophosphamide on longterm reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas. Cancer 70, 270–312.
• 172.Merger D., Tanguay C., Langlois E., Lefebvre M., Bussieres J.F. (2014) Multicenter study of environmental contamination with antineoplastic drugs in 33 Canadian hospitals. Int. Arch. Occup. Environ. Health 87(3), 307–313.
• 173.Mertens R., Rubbert F., Bussing A. (1995) Childhood acute lymphoblastic leukemia (ALL): sister chromatid exchange (SCE) frequency and lymphocyte subpopulations during therapy. Leukemia 9, 501–505.
• 174.Michaud D.S. (2007) Chronic inflammation and bladder cancer. Urol. Oncol. 25, 260–268.
• 175. Miller K. (1991a) Sister-chromatid exchange in human B- and T-lymphocytes exposed to bleomycin, cyclophosphamide, and ethyl methanesulfonate. Mutat. Res. 247, 175–182.
• 176.Miller K. (1991b) Clastogenic effects of bleomycin, cyclophosphamide, and ethyl methanesulfonate on resting and proliferating human B- and T-lymphocytes. Mutat. Res. 251, 241–251.
• 177.Monach P.A., Arnold L.M., Merkel P.A. (2010) Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases. A Data-Driven Review. Arthritis Rheum 62(1), 9–21.
• 178.Mills B.A., Roberts R.W. (1979) Cyclophosphamide- induced cardiomyopathy. A report of two cases and review of the English literature. Cancer 43, 2223–2226.
• 179.Mosienko V.S., Pivnyuk V.M. (1968) Distribution of thio • TEPA and cyclophosphamide in rats and their renal excretion (Buss.). Vrach. Delo 8, 52–54 [Chem. Abstr. 70, 2014b].
• 180.Morse C.C., Sigler C., Lock S., Hakkinen P.J., Haschek W.M., Witschi H.P. (1985) Pulmonary toxicity of cyclophosphamide. A 1-year study. Experim. Mol. Path. 42(2), 251–260.
• 181.Mougeot・Martin M., Krulik M., Harousseau J.L., Audebert A.A., Chaouat Y., Debray J. (1978) Acute leukaemias arising in a case of Behcet's disease and a case of multiple sclerosis treated with immunosuppressors (Fr.). Ann. Med. Intern. (Paris) 129, 175–180.
• 182.Mouridsen H.T., Faber O., Skovsted L. (1974) The biotransformation of cyclophosphamide in man: analysis of the variation in normal subjects. Acta Pharmacol. 35, 98–106.
• 183.Mouridsen H.T., Faber O., Skovsted L. (1976) The metabolism of cyclophosphamide. Dose dependency and the effect of long-term treatment with cyclophosphamide. Cancer 37, 665–670.
• 184.Mulvihill J.J., McKeen E.A., Rosner F., Zarrabi M.H. (1987) Pregnancy outcome in cancer patients. Experience in a large cooperative group. Cancer 60(5), 1143–1150.
• 185.Murthy V.V., Becker B.A., Steele W.J. (1973) Effects of dosage, phenobarbital, and 2-diethylaminoethyl- 2,2-diphenylvalerate on the binding of cyclophosphamide and/or its metabolites to the DNA, RNA, and protein of the embryo and liver in pregnant mice. Cancer Res. 33, 664–670.
• 186.Natarajan A.T., Darroudi F. (1991) Use of human hepatoma cells for in vitro metabolic activation of chemical mutagens/carcinogens. Mutagenesis 6, 399–403.
• 187.Nawar N.N.Y., Sakla F.B., Mahran Z.Y. (1979) Effects of maternal administration of Endoxan, vitamin A and vitamin B 12 on the development of the fetal spinal cord of the albino mouse. Appl. Neurophysiol. 42, 203–211.
• 188.Nicholson H.O. (1968) Leukaemia and pregnancy. A report of five cases and discussion of management. J. Obstet. Gynaecol Br. Commonw 75(5), 517–520.
• 189.NIOSH (1990) National Occupational Exposure Survey (1981–83) National Institute for Occupational Safety and Health. Last updated: 7/1/90 [http://www.cdc.gov/noes/noes1/x3688sic.html].
• 190.NIOSH (2012) List of antineoplastic and other hazardous drugs in healthcare settings. Departament of Health and Human Services. Center for Disease Control and Prevention National Institute for Occupational Safety and Health.
• 191.NTP (2011) Baza danych on-line [http://ntp.niehs.nih.gov/go/roc12].
• 192.NTP (2013) NTP Monograph on developmental effects and pregnancy outcomes associated with cancer chemotherapy used during pregnancy. U.S., Department of Health and Human Services, Division of the National Toxicology Program.
• 193.Opiolka S., Schmidt K. G., Kiffmeyer T., and Schöppe G. (2000) Determination of the vapour pressure of cytotoxic drugs and its effects on occupational safety. Paper presented at The Seventh International Symposium on Oncology Pharmacy Practice. Prague, Czech Republic [cyt. za Kromhout i wsp. 2000].
• 194.Pabst R., Wendler D. (1976) Evaluation of chronic administration of drugs in teratology (Ger.). Anat. Anz. 140, 413–422.
• 195.Paladini D., Vassallo M., D`Armiento M.R., Cianciaruso B., Martinelli P. (2004) Prenatal detection of multiple fetal anomalies following inadvertent exposure to cyclophosphamide in the first trimester of pregnancy. Birth Defects Res (Part A) 70, 99–100.
• 196.Palmer R.G., Smith-Burchnell C.A., Dore C.J., Denman A.M. (1986) Thioguanine-resistant mutations induced by cytotoxic drugs in lymphocytes of patients with connective tissue diseases. Br. J.Rheumatol. 25, 376–379.
• 197.Palmer R.G., Smith-Burchnell C.A., Pelton B.K., Hylton W., Denman A.M. (1988) Use of T cell cloning to detect in vivo mutations induced by cyclophosphamide. Arthritis Rheum. 31, 757–761.
• 198.Pan American Health Organization (2014) Occupational exposure to antineoplastic agent [http://www.occupationalcancer.ca/wp-content/uloads/2014/07/Antineoplastics-and-cancer-ENG.pdf].
• 199.Paolini M., Sapigni E., Hrelia P., Scotti M., Morotti M., Cantelli-Forti G. (1991) Wide spectrum detection of precarcinogens in short-term bioassays by simultaneous superinduction of multiple forms of cytochrome P450 isoenzymes. Carcinogenesis 12, 759–766.
• 200.Paskulin G.A., Ricardo P., Zen G., de Camargo Pinto L.L., Rosa R., Graziadio C. (2005) Combined chemotherapy and teratogenicity. Birth. Defects. Research (Part A) 73(9), 634–637.
• 201.Patel A.R., Shah P.C., Rhee H.L., Sassoon H., Rao K.P. (1976) Cyclophosphamide therapy and interstitial pulmonary fibrosis. Cancer 38, 1542–1549.
• 202.Pedersen-Bjergaard J., Ersboll J., Hansen V.L., Sorensen B.L., Christoffersen K., Hou-Jensen K. I wsp. (1988) Carcinoma of the urinary bladder after treatment with cyclophosphamide for non-Hodgkin’s lymphoma. N. Engl. J. Med. 318, 1028–32.
• 203.Penso J., Lippe B., Ehrlich R., Smith F.G. Jr. (1974) Testicular function in prepubertal and pubertal male patients treated with cyclophosphamide for nephritic syndrome. J. Pediatr. 84, 831–836.
• 204,Petru E., Berger M.R., Schmähl D. (1989) Longterm carcinogenicity of cyclophosphamide in two mouse strains with different spontaneous leukemia incidence. Cancer Lett 44, 221–226.
• 205.Philips F.S., Sternberg S.S., Cronin A.P., Vidal P.M. (1961) Cyclophosphamide and urinary bladder toxicity. Cancer Res. 21, 1577–1589.
• 206.Pizzuto J., Aviles A., Noriega L., Niz J., Morales M., Romero F. (1980) Treatment of acute leukemia during pregnancy: presentation of nine cases. Cancer Treat. Rep. 64(4-5), 679–83.
• 207.Plotz P.H., Klippel J.H., Decker J.L., Grauman D., Wolff B., Brown B.C., Rutt G. (1979) Bladder complications in patients receiving cyclophosphamide for systemic lupus erythematosus or rheumatoid arthritis. Ann. Intern. Med. 91, 221-223.
• 208.Potturi B.R., Singh S., Sanyal A.K. (1975) Ossification patterns of sternum in rat fetuses after maternal administration of cyclophosphamide. Congenital Anomalies 15, 99–106.
• 209.Povirk L.F., Shuker D.E. (1994) DNA damage and mutagenesis induced by nitrogen mustards. Mutat. Res. 318, 205–226.
• 210.Pucci E., Matozzo F., Luppi P., Micoli G., Sottani C., Minoia C., Sandrini G., Nappi G. (2005) Headache as a „sentinel” symptom in personnel involved in the preparation and administration of antineoplastic drugs. G. Ital. Med. Lav. Ergon. 27(4), 412– 416.
• 211.Radis C.D., Kahl L.E., Baker G.L., Wasko M.C., Cash J.M., Gallatin A. i wsp. (1995) Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis: a 20-year followup study. Arthritis Rheum. 38, 1120–7.
• 212.Ramphal R., Bains T., Vaillancourt R. i wsp. (2014) Occupational exposure to cyclophosphamide in nurses at a single center. JOEM 56(3), 304–312.
• 213.Raport z działalności konsultanta krajowego w dziedzinie pielęgniarstwa onkologicznego w 2010 roku [http://www2.mz.gov.pl/wwwfiles/ma_struktura/docs/raport_piel_6_26042011.pdf].
• 214.Raposa T., Várkonyi J. (1987) The relationship between sister chromatid exchange induction and leukemogenicity of different cytostatics. Cancer Detect Prev 10, 141–151.
• 215.Reinhold-Keller E., Beuge N., Latza U., de Groot K., Rudert H., Nolle B. i wsp. (2000) An interdisciplinary approach to the care of patients with Wegener’s granulomatosis: long-term outcome in 155 patients. Arthritis Rheum 43, 1021–32.
• 216.Rekhadevi P.V., Sailaja N., Chandrasekhar M., Mahboob M., Rahman M.F., Grover P. (2007) Genotoxicity assessment in oncology nurses handling anti-neoplastic drugs. Mutagenesis 22, 395–401.
• 217.Reynoso E.E., Shepherd F.A., Messner H.A., Farquharson H.A., Garvey M.B., Baker M.A. (1987) Acute leukemia during pregnancy: the Toronto Leukemia Study Group experience with long-term follow-up of children exposed in utero to chemotherapeutic agents. J. Clin. Oncol. 5(7), 1098–1106.
• 218.Ridola V., Fawaz O., Aubier F., Bergeron C., de Vathaire F., Pichon F., Orbach D., Gentet J.C., Schmitt C., Dufour C., Oberlin O. (2009) Testicular function of survivors of childhood cancer: a comparative study between ifosfamide and cyclophosphamidebased cregimens. Eur. J. Cancer 45(5), 814–8.
• 219.Roberts M.M., Bell R. (1976) Acute leukaemia after immunosuppressive therapy. Lancet 308 (7989), 768–770.
• 220.Roberts J.J., Brent T.P., Crathorn A.R. (1968) The mechanism of the cytotoxic action of alkylating agents on mammalian cells [W:] The Interaction of drugs and subcellular components in animal cells. London, Churchill 5–27 [cyt. za IARC 1981].
• 221.Roscher E., Wiebel F.J. (1988) Mutagenicity, clastogenicity and cytotoxicity of procarcinogens in a rat hepatoma cell line competent for xenobiotic metabolism. Mutagenesis 3, 269–276.
• 222.Roschlau G., Justus J. (1971) Carcinogenic effect of methotrexate and cyclophosphamide in animal experiment. Dtsch Gesundheitsw 26, 219–222.
• 223.Rozporządzenie ministra zdrowia i opieki społecznej z dnia 11.09.1996 r. w sprawie czynników rakotwórczych w środowisku pracy oraz nadzoru nad stanem zdrowia pracowników. DzU nr 121, poz. 571.
• 224.Rozporządzenie ministra zdrowia z dnia 1.12.2004 r. w sprawie substancji, preparatów, czynników lub procesów technologicznych o działaniu rakotwórczym lub mutagennym w środowisku pracy. DzU nr 280, poz. 2771.
• 225.Rozporządzenie ministra zdrowia z dnia 24.07.2012 r. w sprawie substancji chemicznych, ich mieszanin, czynników lub procesów technologicznych o działaniu rakotwórczym lub mutagennym w środowisku pracy. DzU nr 147, poz. 890.
• 226.Rozporządzenie Parlamentu Europejskiego i Rady (WE) nr 1272/2008 z dnia 16 grudnia 2008 r. w sprawie klasyfikacji, oznakowania i pakowania substancji i mieszanin (CLP), zmieniające i uchylające dyrektywy 67/548/EWG i 1999/45/WE oraz zmieniające rozporządzenie (WE) nr 1907/2006. Dz. Urz. WE L 353/2 z 31 grudnia 2008 r., z późn. zm.
• 227.RTECS (2014) Baza danych on-line [http://csi.micromedex.com/].
• 228.Rubes J., Kucharová S., Vozdová M., Musilová P., Zudová Z. (1998) Cytogenetic analysis of peripheral lymphocytes in medical personnel by means of FISH. Mutat. Res. 412, 293–298.
• 229.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.
• 230.Sakata T., Smith R.A., Garland E.M., Cohen S.M. (1989) Rat urinary bladder epithelial lesions induced by acrolein. J. Environ. Pathol. Toxicol. Oncol. 9, 159–169.
• 231.Sanderson B.J., Johnson K.J., Henner W.D. (2001) Induction of mutant lymphocytes in cyclophosphamide- and chlorambucil-treated patients. Mutagenesis 16, 197–202.
• 232.Sardaş S., Erdoğan F., Sardaş O.S., Cengel M., Karakaya A.E. (1994) Sister chromatid exchange studies for monitoring DNA damage in lymphocytes of malignant lymphoma patients under cytostatic therapy. Anticancer Drugs 5, 487–489.
• 233.Sargent E.V., Naumann B.D., Dolan D.G., Faria E.C., Schulman L. (2002) The importance of human data in the establishment of Occupational Exposure Limits. Hum. Ecol. Risk. Assess 8(4), 805–822.
• 234.Schardein J.L. (2000) Chemically Induced Birth Defects. 3rd ed., Marcel Dekker, Inc. NewYork and Basel 585 [cyt. za REPROTOX 2014)].
• 235.Schaumloffel E., Clausnitzer M., Kreyling H. (1975) Radiochromatographic investigation on the metabolism of 3 H-cyclophosphamide in sheep (Ger.). Arzneimittel-Forsch./Drug. Res. 25, 1385–1392.
• 236.Schmähl D. (1967) Carcinogenic action of cyclophosphamide and triaziquone in rats. Dtsch. Med. Wochenschr 92, 1150–1152.
• 237.Schmähl D. (1974) Investigations on the influence of immunodepressive means on the chemical carcinogenesis in rats. Z Krebsforsch Klin. Onkol. Cancer Res. Clin. Oncol. 81, 211–215.
• 238.Schmähl D., Habs M.R. (1979) Carcinogenic action of low-dose cyclophosphamide given orally to Sprague-Dawley rats in a lifetime experiment. Int. J. Cancer 23, 706–712.
• 239.Schmähl D., Habs M.R. (1983) Prevention of cyclophosphamide- induced carcinogenesis in the urinary bladder of rats by administration of mesna. Cancer Treat. Rev. 10, A57–61.
• 240.Schmähl D., Osswald H. (1970) Experimental studies on the carcinogenic effects of anticancer chemotherapeutics and immunosuppressive agents. Arzneimittelforschung 20, 1461–1467.
• 241.Schmidt W., Kreutz R., Wendler D., Gabler W. (1977) Production of skeletal defects after administration of aminoacetonitrile and cyclophosphamide during fetogenesis in rats (Ger.). Verh. Anat. Ges. 71, 635–638.
• 242.Schmitz R., Busch W., von Kreybig T. (1972) Chemically produced malformations of the jaws in animal experiments. I. Action of cyclophosphamide and 6- mercaptopurine on embryonal and fetal development of rats. Dtsch. Zahnheilkd. Mundheilkd. Kieferheilkd. 59, 385–398.
• 243.Seidenfeld A.M., Smythe H.A., Ogryzlo M.A., Urowitz M.B., Dotten D.A. (1976) Acute leukemia in rheumatoid arthritis treated with cytotoxic agents. J. Rheumatol. 3, 295–304.
• 244.Selevan S.G., Undbohm 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, 117–138.
• 245.Sessink P.J., Anzion R.B., van den Broek P.H.H., Bos R.B. (1992) Detection of contamination with antineoplastic agents in a hospital pharmacy department. Pharm. Weekbl. [Sci] 14(1), 16–22.
• 246.Sessink P.J., van den Broek P.H.H., Bos R.P. (1991) Urinary cyclophosphamide excretion in rats after intratracheal, dermal, oral and intravenous administration of cyclophosphamide. J. Appl. Toxicol. 11, 125–128.
• 247.Sessink P.J., Cerná M., Rössner P., Pastorková A., Bavarová H., Franková K., Anzion R.B., Bos R.P. (1994) Urinary cyclophosphamide excretion and chromosomal aberrations in peripheral blood lymphocytes after occupational exposure to antineoplastic agents. Mutat. Res. 309, 193–199.
• 248.Sessink P.J.M., Kroese E.D., van Kranen H.J. (1995) Cancer risk assessment for health care workers occupationally exposed to cyclophosphamide. Int. Arch. Occup. Environ. Health 67, 317–323.
• 249.Sessink P.J., van de Kerkhof M.C.A., Anzion R.B.M., Noordhoek J., Bos R.B. (1994) Environmental contamination and assessment of exposure to antineoplastic agents by determination of cyclophosphamide in urine of exposed pharmacy technicians. Is Skin Absorption an Important Route? Arch. Environ. Health 49(3), 163–169.
• 250.Sessink P.J., Wittenhorst B.C.J., Anzion R.B.M., Bos R.B. (1997) Exposure of pharmacy technicians to antineoplastic agents. Reevaluation after Additional Protective Measures. Arch. Environ. Health 52(3), 240–244.
• 251.Shah P.C., Rao K.R.P., Patel A.R. (1975) Cyclophosphamide- induced nail pigmentation. Lancet 306 (7934), 548–549.
• 252.Sharon N., Neumann Y., Kenet G., Schachter J., Rechavi G., Toren A. (2001) Successful pregnancy after highdose cyclophosphamide and ifosfamide treatment in two postpubertal women. Pediatr. Hematol. Oncol. 18, 247–52.
• 253.Sheibani K., Bukowski R.M., Tubbs R.R., Savage R.A., Sebek B.A., Hoffman G.C. (1980) Acute non lymphocytic leukemia in patients receiving chemotherapy for nonmalignant diseases. Hum. Pathol. 11, 175–179.
• 254.Shimkin M.B., Weisburger J.H., Weisburger E.K., Gubnareff N., Suntzeff V. (1966) Bioassay of 29 alkylating chemicals by the pulmonary-tumor response in strain A Mice. J. Natl. Cancer. Inst. 36, 915–935.
• 255.Sieniawski M., Reineke T., Nogova L., Josting A., Pfistner B., Diehl V., Engert A. (2008) Fertility in male patients with advanced Hodgkin lymphoma treated with BEACOPP: a report of the German Hodgkin Study Group (GHSG). Blood 111(1), 716.
• 256.Silver R.M., Warrick J.H., Kinsella M.B., Staudt L.S., Baumann M.H., Strange C. (1993) Cyclophosphamide and low-dose prednisone therapy in patients with systemic sclerosis (scleroderma) with interstitial lung disease. J. Rheumatol. 20, 838–44.
• 257.Singh S. (1971) The teratogenicity of cyclophosphamide (Endoxan-asta) in rats. Indian J. Med. Res. 59, 1128–1135.
• 258.Singh S., Sanyal A.K. (1976) Eye anomalies induced by cyclophosphamide in rat fetuses. Acta anat. 94, 490–496.
• 259.Singh S., Singh M. (1975) Histochemical changes in the malformed forelimbs of rat fetuses induced by cyclophosphamide. J. Anat. Soc. India 24, 53–59.
• 260.Skowroń J., Czerczak S. (2013) Zasady ustalania dopuszczalnych poziomów narażenia dla czynników rakotwórczych w środowisku pracy w Polsce i w krajach Unii Europejskiej. Med. Pracy 64 (4), 541–563.
• 261.Sladek N.E. (1971) Metabolism of cyclophosphamide by rat hepatic microsomes. Cancer Res. 31, 901–908.
• 262.Smith R.E., Bryant J., DeCillis A., Anderson S. (2003) Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience. J. Clin. Oncol. 21, 1195–1204.
• 263.Soler-Niedziela L., Ong T., Krishna G. Petersen M., Nath J. (1989). Sisterchromatid exchange studies on direct- and indirectacting clastogens in mouse primary cell cultures. Mutat. Res. 224, 465–470.
• 264.Sorsa M., Pyy L., Salomaa S., Nylund L., Yager J.W. (1988) Biological and environmental monitoring of occupational exposure in industry and hospitals. Mutat. Res. 204, 465–479.
• 265.Souliotis V.L., Dimopoulos M.A., Sfikakis P.P. (2003) Genespecific formation and repair of DNA monoadducts and interstrand cross-links after therapeutic exposure to nitrogen mustards. Clin. Cancer Res. 9, 4465–4474.
• 266.Spielmann H., Eibs H.G. (1978) Recent progress in teratology. A survey of methods for the study of drug actions during the preimplantation period. Arzneimittel-Forsch./Drug Res. 28, 1733–1742.
• 267.Spielmann H., Eibs H.G., Merker H.J. (1977) Effects of cyclophosphamide treatment before implantation on the development of rat embryos after implantation. J. Embryol. Expo. Morphol. 41, 65–
• 268.Starzl T.E., Groth C.G., Putnam C.W., Corman J., Halgrimson C.G., Penn I., Husberg B., Gustafsson A., Cascardo S., Geis P., Iwatsuki S. (1973) Cyclophosphamide for clinical renal and hepatic transplantation. Transplant. Proc. 5, 511–516.
• 269.State of California (1993) Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65). No Significant Risk Levels for Carcinogens and Acceptable Intake Levels for Reproductive Toxicants (Status Report). 22 Cal. Code of Reg. Section 12705(d). August.
• 270.Steele T.H., Serpick A.A., Block J.B. (1973) Antidiuretic response to cyclophosphamide in man. J. Pharmacol. Expo Ther. 185, 245–253.
• 271.Stekar J. (1973) Teratogenicity of cyclophosphamide in newborn rats. Arzneimittel-Forsch./Drug Res. 23, 922–923.
• 272.Stillwell T.J., Benson R.C. Jr., DeRemee R.A., McDonald T.J., Weiland L.H. (1988) Cyclophosphamide- induced bladder toxicity in Wegener’s granulomatosis. Arthritis Rheum 31, 465–70.
• 273.Stoichkova N., Damyanov B., Astardzhieva Z. (1979) Ultrastructural changes in the liver of Yoshida tumour rats exposed to cyclophosphamide (Russ.). Vop. Onkol. 25, 88–92.
• 274.Stott H., Fox W., Girting D.J., Stephens R.J., Galton D.A.G. (1977) Acute leukaemia after busulphan. Br. Med. J. 2, 1513–1517.
• 275.Struck R.F. (1974) Isolation and identification of a stabilized derivative of aldophosphamide, a major metabolite of cyclophosphamide. Cancer Res. 34, 2933–2935.
• 276.Struck R.F., Laster W.R. Jr. (1975) Cyclophosphamide (CPA) metabolites in mouse blood (Abstract no. 70). Proc. Am. Assoc. Cancer Res. 16, 18.
• 277.Symington G.R., Mackay I.R., Lambert R.P. (1977) Cancer and teratogenesis: infrequent occurrence after medical use of immunosuppressive drugs. Aust. N. Z. J. Med. 7, 368–372.
• 278.Talar-Williams C., Hijazi Y.M., Walther M.M., Linehan W.M., Hallahan C.W., Lubensky I. i wsp. (1996) Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann. Intern. Med. 124, 477–84.
• 279.Talha M.R.Z., Rogers H.J., Trounce J.R. (1980) Distribution and pharmacokinetics of cvclophosphamide in the rat. Br. J. Cancer 41, 140–143.
• 280.Tanimura M., Yamada K., Sugiura S., Mori K., Nagata H., Tadokoro K., Miyake T., Hamaguchi Y., Sessink P., Nabeshima T. (2009) An environmental and biological study of occupational exposure to cyclophosphamide in in the pharmacy of a Japanese Community Hospital Designated to Treatment of Cancer. J. Health Science 55(5), 750–756.
• 281.Tannenbaum H., Schur P.H. (1974) Development of reticulum cell sarcoma during cyclophosphamide therapy. Arthritis Rheum. 17, 15–18.
• 282.Tates A.D., van Dam F.J., Natarajan A.T., Zwinderman A.H., Osanto S. (1994) Frequencies of HPRT mutants and micronuclei in lymphocytes of cancer patients under chemotherapy: a prospective study. Mutat. Res. 307, 293–306 [cyt. za IARC 2011].
• 283.Tchernia G., Mielot F., Subtil E., Parmentier C. (1976) Acute myeloblastic leukemia after immunedepressive therapy for primary nonmalignant disease. Blood Cells 2, 67–80.
• 284.Te C., Gentile J.M., Baguley B.C., Pearson A.E., Gregory T., Ferguson L.R. (1997) In vivo effects of chlorophyllin on the antitumour agent cyclophosphamide. Int. J. Cancer 70, 84–89 [cyt. za IARC 2011].
• 285.Tokuoka S. (1965) Induction of tumor in mice with N,N-bis(2-chloroethyl)-N’,O-propylenephosphoric acid ester diamide (cyclophosphamide). Gann 56, 537–541.
• 286.Toledo T.M., Harper R.C., Moser R.H. (1971) Fetal effects during cyclophosphamide and irradiation therapy. Ann. intern. Med. 74, 87–91.
• 287.Torkelson A.R., LaBudde J.A., Weikel J.H. Jr. (1974) The metabolic fate of cyclophosphamide. Drug. Metab. Rev. 3, 131–165.
• 288.Townes A.S., Sowa J.M., Shulman L.E. (1976) Controlled trial of cyclophosphamide in rheumatoid arthritis. Arthritis Rheum. 19, 563–73.
• 289.Trasler J.M., Hales B.F., Robaire B. (1985) Paternal cyclophosphamide treatment of rats causes fetal loss and malformations without affecting male fertility. Nature 316, 1441–46.
• 290.Travis L.B., Curtis R.E., Glimelius B., Holowaty E.J., van Leeuwen F.E., Lynch C.F. i wsp. (1995) Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin’s lymphoma. J. Natl. Cancer Inst. 87(7), 524-–530.
• 291.Trenz K., Lugowski S., Jahrsdörfer U. (2003) Enhanced sensitivity of peripheral blood lymphocytes from women carrying a BRCA1 mutation towards the mutagenic effects of various cytostatics. Mutat Res, 544, 279–288; doi:10.1016/j.mrrev. 2003.06.011 PMID:14644329 [cyt. za IARC 2011].
• 292.Tsutsui T.W., Inaba T., Fisher L.W., Robey P.G., Tsutsui T. (2006) In vitro chromosome aberration tests using human dental pulp cells to detect the carcinogenic potential of chemical agents. Odontology 94, 44–50 [cyt. za IARC 2011].
• 293.Turchi G., Nardone A., Palitti F. (1992) Application of an epithelial liver cell line, metabolically competent, for mutation studies of promutagens. Mutat. Res. 271, 79–88.
• 294.Turci R., Sottani C., Ronchi A., Minoia C. (2002) Biological monitoring of hospital personnel occupationally exposed to antineoplastic drugs. Toxicology Letters 134, 57–64.
• 295.Turci R., Minoia C., Sottani C., Coghi R., Severi P., Castriotta C., Del Bianco M., Imbriani M. (2010) Occupational exposure to antineoplastic drugs in seven Italian hospitals. The effect of of quality assurance and adherence to guidelines. J. Oncol. Pharm. Practice 17(4), 320–332.
• 296.Uldall P.R., Kerr D.N.S., Tacchi D. (1972) Sterility and cyclophosphamide. Lancet 1, 693–694.
• 297.Ujhazy E., Prelnerova M., Jozefik M. (1979) Effects of cyclophosphamide on the prenatal development of the Swiss strain mice. Neoplasma 26, 529–537.
• 298.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. Am. J. Hosp. Pharm. 50(3), 455–462.
• 299.Vaux K.K., Kahole N.C., Jones K.L. (2003) Cyclophosphamide, methotrexate, and cytarabine embropathy: is apoptosis the common pathway? Birth. Defects Res. A. Clin. Mol. Teratol. 67(6), 403–408.
• 300.Voelcker G., Wagner T., Hohorst H.J. (1976) Identification and pharmacokinetics of cvclophosphamide (NSC•26271) metabolites in vivo. Cancer Treat. Rep. 60, 415–422.
• 301.Wagner T., Heydrich D., Voelcker G., Hohorst H.J. (1980) Blood level and urinary excretion of activated cyclophosphamide and its deactivation products in man (Ger.) J. Cancer Res. Clin. Oncol. 96, 79–92.
• 302.Walker S.E., Anver M.R. (1979) Accelerated appearance of neoplasms in female NZB/NZW mice treated with high-dose cyclophosphamide. Arthritis Rheum. 22, 1338–1343.
• 303.Walker S.E., Anver M.R. (1983) High incidence of neoplasms in female NZB/NZW mice treated with pulse doses of cyclophosphamide. Vet Immunol Immunopathol 5, 97–104.
• 304.Walker S.E., Bole G.G. (1971) Augmented incidence of neoplasia in female New Zealand black- New Zealand white (NZB-NZW) mice treated with long-term cyclophosphamide. J. Lab. Clin. Med. 78, 978–979.
• 305.Walker S.E., Bole G.G. Jr. (1973) Augmented incidence of neoplasia in NZB-NZW mice treated with longterm cyclophosphamide. J. Lab. Clin. Med. 82, 619–633.
• 306.Watson A.R., Rance C.P., Bain J. (1985) Long term effects of cyclophosphamide on testicular function. Br. Med. J. 291, 14571–460.
• 307.Weisburger J.H., Griswold D.P., Prejean J.D., Casey A.E., Wood H.B., Weisburger E.K. (1975) The carcinogenic properties of some of the principal drugs used in clinical cancer chemotherapy. Recent. Results. Cancer Res. 52, 1–17.
• 308.de Werk Neal A., Wadden R.A., Chiou W.L. (1983) Exposure of Hospital Workers to Airborne Antineoplastic Agents. Am. J. Hosp. Pharm. 40, 597–601.
• 309.Westman K.W., Bygren P.G., Olsson H., Ranstam J., Wieslander J. (1998) Relapse rate, renal survival, and cancer morbidity in patients with Wegener’s granulomatosis or microscopic polyangiitis with renal involvement. J. Am. Soc. Nephrol. 9, 842–52.
• 310.Wheeler G.P. (1962) Studies related to the mechanisms of action of cytotoxic alkylating agents: a review. Cancer Res. 22, 651–688.
• 311.Wheeler A.G., Dansby D., Hawkins H.C., Payne H.G., Weikel J.H. Jr. (1962) A toxicologic and hematologic evaluation of cyclophosphamide (Cytoxan ®) in experimental animals. Toxicol. Appl. Pharmacol. 4, 324–343.
• 312.Wiernik P.H., Duncan J.H. (1971) Cyclophosphamide in human milk. Lancet 1, 912.
• 313.Willson J.K.V. (1978) Pulmonary toxicity of antineoplastic drugs. Cancer Treat. Rep. 62, 2003– 2008.
• 314.Wilmer J.L., Erexson G.L., Kligerman A.D. (1990) Effect of acrolein on phosphoramide mustard-induced sister chromatid exchanges in cultured human lymphocytes. Cancer Res. 50, 4635–4638.
• 315.Winckler K., Obe G., Madle S., Kocher-Becker U., Kocher W., Nau H. (1987) Cyclophosphamide: interstrain differences in the production of mutagenic metabolites by S9-fractions from liver and kidney in different mutagenicity test systems in vitro and in the teratogenic response in vivo between CBA and C57 BL mice. Teratog. Carcinog. Mutagen 7, 399– 409.
• 316.Worlledge S.M., Brain M.C., Cooper A.C., Hobbs J.R., Dacie J.V. (1968) Immunosuppressive drugs in the treatment of autoimmune haemolytic anaemia. Proc. R. Soc. Med., 61, 1312–1315.
• 317.Yager J.W., Sorsa M., Selvin S. (1988) Micronuclei in cytokinesis-blocked lymphocytes as an index of occupational exposure to alkylating cytostatic drugs. IARC Sci. Publ. (89), 213–216.
• 318.Yamamoto S., Mitsumori K., Kodama Y., Matsunuma N., Manabe S., Hayashi Y. (1996) Rapid induction of more malignant tumors by various genotoxic carcinogens in transgenic mice harboring a human prototype c-Ha-ras gene than in control non-transgenic mice. Carcinogenesis 17, 2455–2461.
• 319.Yoshinaka A., Fukasawa I., Sakamoto T., Tanaka M., Ota Y., Inaba N. (2000) The fertility and pregnancy outcomes of the patients who underwent preservative operation followed by adjuvant chemotherapy for malignant ovarian tumors. Arch. Gynecol. Obstet. 264, 124–7.
• 320.Zemlickis D., Lishner M., Erlich R., Koren G. (1993) Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide. Teratogenesis Carcinog Mutagen 13, 139–43.
• 321.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.
• 322.Zijlstra J.A., Vogel E.W. (1989) Influence of metabolic factors on the mutagenic effectiveness of cyclophosphamide in Drosophila melanogaster. Mutat. Res. 210, 79–92.
• 323.Zuniga G., Torres-Bugaŕin O., Ramirez-Munoz M.P., Delgado-Lamasa R., De Loza-Saldanab J.M., Cantuc J.M. (1996) Micronucleated erythrocytes in splenectomized patients with and without chemotherapy. Mutat. Res. 361, 107–112.