4.1 Analysis of the results
MMF is the most commonly consumed drug. The main reason behind the elevated consumption of MMF prodrug and its active ingredient MPA is that they are used for as both chemotherapeutic and immunosuppressive agents in organ transplantation as well as auto-immune disease . The analysis of the toxicity of MMF and MPA each separately led to an underestimation of the risks imposed by this drug. Since MMF is a prodrug of MPA, the consumption of both was grouped using drug-specific equivalence factors under a total MPA equivalent (table 1). The PEC values calculated for the MPA equivalent led to risk categorization of the MPA equivalent into either class IIA or class IA for different years, indicating that MPA is a potentially hazardous compound. In contrast, when MPA was analyzed as a separate entity of MMF, it was classified into class IIA and class III for different years, underestimating its potential toxicity. The consumption trend of MMF and MPA was consistent between the years 2013 and 2018. In comparison with global consumption, MMF consumption in Lebanon is 329.22 μg Inhabitant-1 Day-1, lower than its consumption in Portugal (593 μg Inhabitant-1 Day-1) . As for MPA, its consumption in Lebanon equals 72.03287 μg Inhabitant-1 Day-1, higher than in Portugal (50 μg Inhabitant-1 Day-1) )  and Poland (51 μg Inhabitant-1 Day-1)  but lower than in Catalonia (704 μg Inhabitant-1 Day-1) .
The second most commonly consumed drug is hydroxycarbamide. This could be explained by the fact that hydroxycarbamide is highly consumed in the Middle East and Africa region and it is relatively cheaper than other chemotherapeutic drugs and has several indications . Its consumption approximately doubled between the years 2013 and 2018. It was classified, according to the calculated PEC values, in class IIA (potentially hazardous compounds) for the years 2013-2018. In comparison with global consumption, the consumption of hydroxycarbamide in Lebanon is equal to 140.97 μg Inhabitant-1 Day-1, higher than in the UK (33 μg Inhabitant-1 Day-1)  but lower than in Portugal (253 μg Inhabitant-1 Day-1) , Catalonia (221 μg Inhabitant-1 Day-1)  and France (284 μg Inhabitant-1 Day-1) .
The third most commonly consumed drug is Capecitibine. Capecitabine is a widely used chemotherapeutic drug as it has gained approval in two of the most common cancers in Lebanon: breast and colorectal cancer . Additionally, There is a global trend towards the prescribing of capecitabine over fluorouracil as capecitabine allows more patient-friendly oral administration, improved quality of life and fewer side effects . It is worth noting that consumption data of fluorouracil for the years 2014 to 2016 was absent from the provided data. Accordingly, we could not have a clear image on the extent/trend in its consumption. As previously mentioned in the results section, capecitabine is a prodrug of 5-fluorouracil. Accordingly, the consumption of both was grouped using drug-specific equivalence factors under a total 5-fluorouracil equivalent. The PEC values calculated for the equivalent lead to its risk categorization into class IIA for the years 2013-3018, indicating that 5-fluorouracil is a potentially hazardous compound. This again proves that a separate analysis of capecitabine and 5-fluorouracil will lead to an underestimation of the toxicity of each of the drugs, as 5-fluorouracil analyzed separately was classified into class IV (very low risk). The consumption of capecitabine decreased by one-third between the years 2013 and 2018. In comparison with global consumption, the consumption of capecitabine in Lebanon is equal to 133.09 μg Inhabitant-1 Day-1, lower than its consumption in Portugal (206 μg μg Inhabitant-1 Day-1) , Catalonia (280 μg Inhabitant-1 Day-1) , France (213 μg Inhabitant-1 Day-1)  , and UK (183 μg Inhabitant-1 Day-1) . As for 5-fluorouracil, its consumption in Lebanon is equal to 6.69 μg Inhabitant-1 Day-1 and it is higher than its consumption in Catalonia (0.70 μg Inhabitant-1 Day-1)  and lower than Portugal (62.50 μg Inhabitant-1 Day-1) , France (71. μg Inhabitant-1 Day-1)  and UK (46 μg Inhabitant-1 Day-1) .
The fifth most commonly consumed drug is Azathioprine. Azathioprine labeled indications are kidney transplantation and rheumatoid arthritis. Its use can be explained by the wide prevalence of rheumatoid arthritis disease in the Lebanese population versus the global population, 1% and 0.5 to 1%, respectively . Its consumption has remained the same between years 2013 and 2018.Azathioprine was classified, according to the calculated PEC values, in class IIA (potentially hazardous compounds) for the years 2013-2018.
4.2 Actual Risk
In this study, we have analyzed the risk imposed by chemotherapeutic micro-pollutants based on their yearly consumption. However, in fact, some chemotherapeutic drugs accumulate and their amounts in the environment build up over the years, alluding to a higher ecotoxicological risk. A review of the environmental fate of the top 5 most consumed drugs reveals that none of them is a potential bio-accumulative drug [9,28,30]. However, less commonly consumed chemotherapy drugs that can accumulate and potentially pose a serious environmental risk include: Cyclophosphamide, Ifosfamide  and Erlotinib .
Another factor that should be taken into consideration is that the residues of pharmaceuticals occur in the environment as complex mixtures, and therefore, even though the concentrations of an individual compound might be low, the cocktail effect might have a more concerning ecotoxicological implication. Research studies on the environmental concern of combinations of anticancer drugs revealed that the interactions of anticancer drugs could be of environmental concern [33–35].
4.3 Impact on animals/humans
Studies investigating the toxicity of chemotherapy drugs on animals are scarce and are usually done using higher concentrations than those found in the environment. Accordingly, additional work is needed to evaluate the acute and chronic risks associated with exposure to environmental concentrations. MPA risk evaluation studies revealed that it can cause growth inhibition in green algae. The germination as well as root growth of certain seeds was signiﬁcantly inhibited by MPA in a concentration‐dependent manner. Additionally, the exposure of the cyano-bacterium A. ﬂos‐aquae to MPA resulted in a clear concentration–response relationship on the growth rate of the bacteria . A study by Kovacs et al. (2015) evaluated the chronic exposure of zebrafish to 5-Fluorouracil at environmentally relevant concentrations. The results revealed that such exposure causes hepatic and renal histopathological changes, DNA damage and massive whole-transcriptome changes . Another study by Mišík et al. (2016) reports an increased frequency of abortive grains in higher plants exposed to 5-fluorouracil .
In addition, with the geographical location of Lebanon in mind, we cannot but highlight the impact of those micropollutants on neighboring countries that share the Mediterranean Sea, including but not limited to Algeria, Croatia, Cyprus, Egypt, France and Greece.
4.4 The need for regulations
4.4.1 The importance of WWTPs
Pharmaceutical compounds are designed to have desirable target effects in the human body, but the impact of chronic indirect exposure to these compounds can be dangerous for both humans as well as other species. Anticancer drugs have potent cytotoxic, genotoxic, mutagenic, carcinogenic, endocrine disruptor as well as teratogenic effects. The augmentation of cancer disease in the Lebanese population has led to an increase in the drug consumption and therefore an increase in drug discharge into the environment. Therefore, it is indeed essential to pay special attention to the discharge of anticancer drugs in the environment and the development of effective WWTPs. It is worth noting that not all waste water treatment techniques are effective at removing anticancer drugs. The scarce literature available shows that a promising method for the removal of micropollutants is the membrane bioreactor (MBR), which combines physical removal with biological removal (biodegradation) to improve the outcome of the water treatment .
4.4.2 Pharmaceutical waste management in Lebanon
In this paper, we have tackled the risks imposed by a major source of chemotherapeutic drug in surface waters: the chemotherapeutic drugs consumed by the patients in medical centers as well as their home. However, another major source of micropolluants are expired/unused drugs that stay at the importer’s warehouses and do not reach hospitals/patients. In the absence of a safe solution and the necessary regulations to dispose of pharmaceutical surplus, warehouses in Lebanon are filling up with old, expired drugs .
4.4.3 Need for regulations
Efforts are needed to set new policies regarding the disposal of micropollutants in general, and chemotherapeutic drugs primarily. We hope that this research study sheds light on the risk imposed by chemotherapeutic drugs and contributes to future establishment and enforcement of regulations to protect the public from the danger of such micropullutants in surface waters.
4.5 Future studies needed
Our research study is the first of its kind in Lebanon and the Middle East. As previously stated, in this study, we have estimated the environmental concentrations in surface waters by the calculation of PECs based on consumption data. Reports on the occurrence of chemotherapeutic drugs in surface water, ground water or drinking water by measurement of actual of the drug concentrations are absent.