The occurrence of toxic drug residues is a hot topic concerning emerging environmental contaminants. The occupational exposure
to anticancer drugs could be severe for health-care personnel and general public attending potentially polluted areas (such
as oncology departments of hospitals) because of high therapeutic concentrations. The aim of this work was to generate degradation
compounds similar to those formed in metabolic or environmental pathways by adopting a photocatalytic process and to identify
them in indoor environments alongside parent compounds. A photodegradation model was applied to cyclophosphamide and mitomycin
C. Studied substances and degradants were quantified in environmental samples by liquid chromatography with multiple-stage
mass spectrometry (LC–MS
) analysis using an orbital trap instrument with an electrospray interface. Various oxidative degradants were formed using
the photocatalytic simulation model of degradation of antineoplastic drugs, beside some hydrolysis and molecule breakdown
subproducts. High resolution MS
spectra were used to identify and confirm the proposed structures. Kinetics of formation of the main degradation products
were also studied.
The frequency of recognition of toxic drug residues is an important issue concerning emerging environmental contaminants.
This problem is also exacerbated by the low therapeutic index of drugs used in cancer chemotherapy. The occupational exposure
to residues of anticancer drugs must be kept under strict control by safety managers because it could be severe for health
care personnel and general public attending potentially polluted areas (such as oncology departments and pharmacies of hospitals)
because of high therapeutic concentrations. In addition, urinary elimination by patients represents a source of contamination.
The monitoring of drug residues is necessary to guarantee occupational safety and the absence of pollution. The presence of
anticancer drug residues in environmental water samples has been reported (1–3). Looking closer at the structural features
of these compounds, it is possible to see that the majority of chemotherapeutic drugs hold molecular structures with a high
chemical reactivity (4). As a consequence of this great aptitude to undergo chemical transformation, it could be difficult
to record measurable levels of some of these drugs. As an example, in a previous study (5) we found evidence of the difficulty
to recover traces of mitomycin C because of its low stability. The aim of this work is to generate degradation compounds similar
to those formed in metabolic or environmental pathways by adopting a photocatalytic process and to identify them in indoor
environments. An additional purpose of this study is to develop a selective and sensitive method as a tool to detect drug
transformation and degradation products and to quantify them in biological and environmental samples, beside parent compounds.
In this work, two anticancer drugs were studied: the N-mustard cyclophosphamide (N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide) and the aziridine mitomycin C ([(1aS,8S,8aR,8bS)-6-amino-8a-methoxy-5-methyl-4,7-dioxo-1,1a,2,4,7,8,8a,8b-octahydroazireno[2',3':3,4]pyrrolo[1,2-a]indol-8-yl]methyl
carbamate). We chose cyclophosphamide and mitomycin C because of the popular use of these drugs and because of their different
stability. The photodecomposition of drugs was carried out by heterogeneous photocatalysis, using titanium dioxide in water
as previously reported (6,7). By this process, the photodecomposition of drugs could be due to either oxidative species or
reductive conduction band electrons (8,9).
A highly sensitive method was developed to measure the degradation products in wipe samples that allows detection of parent
drugs at the nanogram level (5). Occupational exposure monitoring of these drugs shows frequent cyclophosphamide positive
measurements but no significant mitomycin C determination. The high instability of the mitomycin molecule is probably the
main cause of these findings. One of the targets of this work is to identify new possible markers of mitomycin in environmental
pollution. Identification and characterization of degradation compounds could contribute significantly to the development
of more effective analytical methods to monitor occupational exposure.
High performance liquid chromatography (HPLC) coupled to mass spectrometry (MS) via an electrospray ionization (ESI) interface
is a powerful tool to identify and measure anticancer drugs in the environment (10), especially in health care settings (11).
However, liquid chromatography—mass spectrometry (LC–MS) analysis performed in full-scan mode is not sensitive enough to detect
and characterize metabolites at trace levels and the excellent sensitivity provided in multiple reaction monitoring (MRM)
mode suffers from a lack of structural information to characterize the huge number of potential degradants formed from drug
For this reason, we developed a sensitive liquid chromatography–high-resolution mass spectrometry (LC–HRMS) methodology using
orbital trap technology (12) with the purpose of exploiting the potential of untargeted analysis for which it is fitted. From
the analysis of spectra acquired at high resolving power, it was possible to hypothesize the structure of the main degradation
products observed in the photocatalysis simulation model.