title: Estimation of the cancer risk to humans resulting from the presence of cyclophosphamide and ifosfamide in surface water.
abstract: OBJECTIVE
  Anti-tumour agents and their metabolites are largely excreted into effluent, along with other pharmaceuticals. In the past, investigations have focused on the input and analysis of pharmaceuticals in surface and ground water. The two oxazaphosphorine compounds, cyclophosphamide and ifosfamide are important cytostatic drugs used in the chemotherapy of cancer and in the treatment of autoimmune diseases. Their mechanism of action, involving metabolic activation and unspecific alkylation of nucleophilic compounds, accounts for genotoxic and carcinogenic effects described in the literature and is reason for environmental concern. The anti-tumour agents cyclophosphamide (CP) and ifosfamide (IF) were not biodegraded in biodegradation tests. They were not eliminated in municipal sewage treatment plants. Degradation by photochemically formed HO radicals may be of some relevance only in shallow, clear, and nitrate-rich water bodies but could be further exploited for elimination of these compounds by advanced oxidation processes, i.e. in a treatment of hospital waste water. Therefore, CP and IF are assumed to persist in the aquatic environment and to enter drinking water via surface water. The risk to humans from input of CP and IF into surface water is not known.
  
  
  METHODS
  The local and regional, i.e. nationwide predicted environmental concentration (PEC(local), PEC(regional)) of CP and IF was calculated for German surface water. Both compounds were measured in hospital effluents, and in the influent and effluent of a municipal treatment plant. Additionally, published concentrations in the effluent of sewage treatment plants and surface water were used for risk assessment. Excretion rates were taken into account. For a worst-case scenario, maximum possible ingestion of CP or IF by drinking 2 L a day of unprocessed surface water over a life span of 70 years was calculated for adults. Elimination in drinking water processing was neglected, as no data is available. This intake was compared with intake during anti-cancer treatment.
  
  
  CONCLUSIONS
  Intake of CP and IF for anti-cancer treatment is typically 10 g within a few months. Under such conditions, a relative risk of 1.5 for the carcinogenic compounds CP and IF is reported in the literature. In the worst case, the maximum possible intake by drinking water is less than 10(-3) (IF) and 10(-5) (CP) of this amount, based on highest measured local concentrations. On a nationwide average, the factor is approx. 10(-6) or less.
  
  
  CONCLUSIONS
  The additional intake of CP and IF due to their emission into surface water and its use without further treatment as drinking water is low compared to intake within a therapy. This approach has shortcomings. It illustrates the current lack of methodology and knowledge for the specific risk assessment of carcinogenic pharmaceuticals in the aquatic environment. IF and CP are directly reacting with the DNA. Therefore, with respect to health effects a safe threshold concentration for these compounds cannot be given. The resulting risk is higher for newborns and children than for adults. Due to the lack of data the risk for newborns and children cannot be assessed fully. The data presented here show that according to present knowledge the additional risk of cancer cannot be fully excluded, especially with respect to children. Due to the shortage of data for effects of CP and IF in low doses during a whole lifespan, possible effects were assessed using data of high doses of CP and IF within short-term ingestion, i.e. therapy. This remains an unresolved issue. Anyway, the risk assessment performed here could give a rough measure of the risks on the one hand and the methodological shortcomings on the other hand which are connected to the assessment of the input of genotoxic and carcinogenic pharmaceuticals such as CP and IF into the aquatic environment. Therefore, we recommend to take measures to reduce the input of CP and IF and other carcinogenic pharmaceuticals. We hope that our manuscript further stimulates the discussion about the human risk assessment for carcinogenic pharmaceuticals in the aquatic environment.
  
  
  CONCLUSIONS
  CP and IF are carcinogens. With respect to newborn and children, reduction of the emission of CP and IF into effluent and surface water is recommended at least as a precautionary measure. The collection of unused and outdated drugs is a suitable measure. Collection of patients' excreta as a measure of input reduction is not recommended. Data suitable for the assessment of the risk for newborn and children should be collected in order to perform a risk assessment for these groups. This can stimulate discussion and give new insights into risk assessment for pharmaceuticals in the environment. Our study showed that in the long term, effective risk management for the reduction of the input of CP and IF are recommendable.
authors: Department of Environmental Health Sciences, University Medical Centre Freiburg, Breisacherstrasse 115b, 79106, Freiburg, Germany. Klaus.Kuemmerer@uniklinik-freiburg.de
authors: Klaus
authors: K
authors: Kümmerer
authors: Ali
authors: A
authors: Al-Ahmad
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000032:analysis; D002274:Carcinogens, Environmental / Q000032:analysis*; D003520:Cyclophosphamide / Q000032:analysis* / Q000737:chemistry; D004781:Environmental Exposure / Q000032:analysis; D004784:Environmental Monitoring; D005618:Fresh Water / Q000737:chemistry*; D006801:Humans; D007069:Ifosfamide / Q000032:analysis* / Q000737:chemistry; D016017:Odds Ratio; D018570:Risk Assessment; D012722:Sewage / Q000737:chemistry; D014865:Waste Disposal, Fluid; D014874:Water Pollutants, Chemical / Q000032:analysis*; D014881:Water Supply / Q000032:analysis
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002274:Carcinogens, Environmental; D012722:Sewage; D014874:Water Pollutants, Chemical; D003520:Cyclophosphamide; D007069:Ifosfamide