Estimation of the cancer risk to humans resulting from the presence of cyclophosphamide and ifosfamide in surface water
Estimation of the cancer risk to humans resulting from the presence of cyclophosphamide and ifosfamide in surface water
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地表水中环磷酰胺和异环磷酰胺对人类造成癌症风险的估计
DOI：
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发表时间：
2010
期刊：
影响因子：
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通讯作者：
A. Al
中科院分区：
文献类型：
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作者：
K. Kümmerer;A. Al
背景、目的和范围抗肿瘤药物及其代谢物与其他药物一起大量排泄到污水中。过去，调查主要集中在地表水和地下水中药物的输入和分析。两种恶氮磷化合物环磷酰胺和异环磷酰胺是用于癌症化疗和自身免疫性疾病治疗的重要细胞抑制药物。它们的作用机制，涉及代谢激活和亲核化合物的非特异性烷基化，解释了文献中描述的遗传毒性和致癌作用，是引起环境关注的原因。在生物降解试验中，抗肿瘤药物环磷酰胺（CP）和异环磷酰胺（IF）不能被生物降解。它们在城市污水处理厂没有被消除。光化学形成的HO自由基的降解可能仅在浅水、清澈和富含硝酸盐的水体中具有一定的相关性，但可以进一步利用高级氧化过程来消除这些化合物，即在医院废水的处理中。因此，假设CP和IF在水生环境中持续存在，并通过地表水进入饮用水。向地表水输入CP和IF对人类的风险尚不清楚。材料与方法计算德国地表水CP和IF的局部和区域（即全国）预测环境浓度（PEClocal, pecregion）。这两种化合物都在医院污水和市政处理厂的污水中进行了测量。此外，将公布的污水处理厂流出物和地表水的浓度用于风险评估。排泄率也被考虑在内。在最坏的情况下，计算了成年人在70年的寿命中每天饮用2升未经处理的地表水所可能摄入的最大CP或IF。由于没有数据，饮用水处理中的消除被忽视。这一摄入量与抗癌治疗期间的摄入量进行了比较。结果和讨论抗癌治疗的CP和IF的摄入量通常在几个月内为10克。在这种情况下，文献报道致癌化合物CP和IF的相对风险为1.5。在最坏的情况下，根据当地测量的最高浓度，饮用水的最大可能摄入量小于该量的10−3 （IF）和10−5 （CP）。在全国范围内，这个因素大约是。10−6以下。结论由于排放到地表水和未经进一步处理而作为饮用水使用的CP和IF的额外摄入量与治疗期间的摄入量相比较低。这种方法有缺点。它说明了目前缺乏对水生环境中致癌性药物的具体风险评估的方法和知识。IF和CP直接与DNA反应。因此，就对健康的影响而言，无法给出这些化合物的安全阈值浓度。新生儿和儿童的风险高于成人。由于缺乏数据，无法充分评估新生儿和儿童的风险。这里提供的数据表明，根据目前的知识，不能完全排除癌症的额外风险，特别是对儿童而言。由于缺乏低剂量CP和IF在整个生命周期内的影响数据，因此使用短期摄入（即治疗）高剂量CP和IF的数据来评估可能的影响。这仍然是一个未解决的问题。无论如何，这里进行的风险评估一方面可以给出风险的粗略衡量，另一方面可以给出与遗传毒性和致癌药物（如CP和IF）进入水生环境的评估相关的方法缺陷。因此，我们建议采取措施减少CP和IF等致癌药物的投入。我们希望我们的稿件能进一步激发关于水生环境中致癌药物的人类风险评估的讨论。建议和观点cp和IF是致癌物。对于新生儿和儿童，建议至少作为一项预防措施，减少向污水和地表水排放CP和IF。收集未使用和过期药品是一种合适的措施。不建议收集患者排泄物作为减少输入的措施。应收集适合评估新生儿和儿童风险的数据，以便对这些群体进行风险评估。这可以激发讨论，并为药物在环境中的风险评估提供新的见解。我们的研究表明，从长远来看，有效的风险管理减少CP和IF的投入是值得推荐的。
Background, aim, and scopeAnti-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.Materials and methodsThe local and regional, i.e. nationwide predicted environmental concentration (PEClocal, PECregional) 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.Results and discussionIntake 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.ConclusionsThe 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.Recommendations and perspectivesCP 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.
高效液相色谱法测定尿异环磷酰胺 2- 和 3- 脱氯乙基化代谢物。
DOI：
10.1016/0378-4347(91)80538-n
发表时间：
1991
期刊：
Journal of chromatography
影响因子：
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作者：
Goren,MP
通讯作者：
Goren,MP