Rik Oldenkamp

Do Concentrations of Ethinylestradiol, Estradiol, and Diclofenac in European Rivers Exceed Proposed EU Environmental Quality Standards?

This study used a geographic based water model to predict the environmental concentrations of three pharmaceuticals, 17α-ethinylestradiol (EE2), 17β-estradiol (E2), and diclofenac throughout European rivers. The work was prompted by the proposal of the European Community (COM(2011)876) to consider these chemicals as candidates for future control via environmental quality standards (EQS). National drug consumption information, excretion, national water use, and sewage removal rates, were used to derive per capita sewage effluent values for the European countries . For E2, excretion rates of the natural hormone and national demographics were also included. Incorporating this information into the GWAVA model allowed water concentrations throughout Europes rivers to be predicted. The mean concentration from the expected sewage discharge scenario indicated that 12% by length of Europes rivers would reach concentrations greater than the proposed 0.035 ng/L EQS for EE2. For several countries, between a quarter and a third of their total river length would fail such an EE2 EQS. For E2, just over 1% by length of rivers would reach concentrations greater than the 0.4 ng/L proposed EQS, while just over 2% by length of rivers would reach concentrations greater than the proposed EQS of 100 ng/L for diclofenac.

Cumulative risk assessment of chemical exposures in urban environments

We performed a cumulative risk assessment for people living in a hypothetical urban environment, called Urbania. The main aims of the study were to demonstrate how a cumulative risk assessment for a middle-sized European city can be performed and to identify the bottlenecks in terms of data availability and knowledge gaps. The assessment focused on five air pollutants (i.e., PM₁₀, benzene, toluene, nonane and naphthalene) and six food pesticides (i.e., acetamiprid, carbendazim, chlorpyrifos, diazinon, imidacloprid and permethrin). Exposure predictions showed that PM₁₀, benzene and naphthalene exposure frequently exceeded the standards, and that the indoor environment contributed more than the outdoor environment. Effect predictions showed that mixture and interaction effects were generally limited. However, model calculations indicated potential synergistic effects between naphthalene and benzene and between chlorpyrifos, diazinon and toluene. PM₁₀ dominated the health impact expressed in Disability Adjusted Life Years (DALYs). We conclude that measures to reduce the health impact of environmental pollution should focus on the improvement of indoor air quality and the reduction of PM₁₀ emissions. Cumulative risk assessment can be improved by (1) the development of person-oriented exposure models that can simulate the cumulative exposure history of individuals, (2) a better mechanistic understanding of the effects of cumulative stressors, and (3) the development of instruments to prioritize stressors for inclusion in cumulative risk assessments.

Valuing the human health damage caused by the fraud of Volkswagen.

Recently it became known that Volkswagen Group has been cheating with emission tests for diesel engines over the last six years, resulting in on-road emissions vastly exceeding legal standards for nitrogen oxides in Europe and the United States. Here, we provide an estimate of the public health consequences caused by this fraud. From 2009 to 2015, approximately nine million fraudulent Volkswagen cars, as sold in Europe and the US, emitted a cumulative amount of 526 ktonnes of nitrogen oxides more than was legally allowed. These fraudulent emissions are associated with 45 thousand disability-adjusted life years (DALYs) and a value of life lost of at least 39 billion US dollars, which is approximately 5.3 times larger than the 7.3 billion US dollars that Volkswagen Group has set aside to cover worldwide costs related to the diesel emissions scandal.

Spatially explicit prioritization of human antibiotics and antineoplastics in Europe

This paper presents a screening tool for the location-specific prioritization of human pharmaceutical emissions in Europe, based on risk quotients for the aquatic environment and human health. The tool provides direction towards either monitoring activities or additional research. Its application is illustrated for a set of 11 human antibiotics and 7 antineoplastics. Risk quotients for the aquatic environment were highest for levofloxacin, doxycycline and ciprofloxacin, located in Northern Italy (Milan region; particularly levofloxacin) and other densely populated areas in Europe (e.g. London, Krakow and the Ruhr area). Risk quotients for human health not only depend on pharmaceutical and location, but also on behavioral characteristics, such as consumption patterns. Infants in eastern Spain that consume locally produced food and conventionally treated drinking water were predicted to run the highest risks. A limited comparison with measured concentrations in surface water showed that predicted and measured concentrations are approximately within one order of magnitude.

Predicting concentrations of the cytostatic drugs cyclophosphamide, carboplatin, 5-fluorouracil, and capecitabine throughout the sewage effluents and surface waters of Europe.

The present study evaluated the potential environmental concentrations of 4 cytostatic (also known as cytotoxic) drugs in rivers. The antimetabolite 5-fluorouracil (5FU) and its pro-drug capecitabine were examined based on their very high use rates, cyclophosphamide (CP) for its persistence, and carboplatin for its association with the metal element platinum. The study combined drug consumption information across European countries, excretion, national water use, and sewage removal rates to derive sewage effluent values across the continent. Results showed considerable variation in the popularity of individual cytostatic drugs across Europe, including a 28-fold difference in 5FU use and 15-fold difference in CP use. Such variations could have a major effect on the detection of these compounds in effluent or river water. Overall, capecitabine and CP had higher predicted levels in effluent than 5FU or carboplatin. Predicted effluent values were compared with measurements in the literature, and many non-detects could be explained by insufficient limits of detection. Linking the geographic based water resources model GWAVA with this information allowed water concentrations throughout 1.2 million km of European rivers to be predicted. The 90th percentile (worst case) prediction indicated that, with the exception of capecitabine, more than 99% of Europes rivers (by length) would have concentrations below 1 ng/L for these cytostatic drugs. For capecitabine, 2.2% of river length could exceed 1 ng/L.

Separating uncertainty and physiological variability in human PBPK modelling: The example of 2-propanol and its metabolite acetone.

Parameter uncertainty and interindividual variability in the predictions of a generic human physiologically based pharmacokinetic (PBPK) model were separated by means of nested Monte Carlo simulations. Separate information on uncertainty and variability can help decision makers to identify whether they should focus on identification of sensitive individuals rather than on additional research to obtain more accurate estimates for particular parameters. In this study, the concentration of acetone in human blood was simulated during and after 4h of exposure to 2-propanol via air. It was shown that the influence of interindividual variability and uncertainty varies over time, from the uptake phase, via a steady-state phase, into the elimination phase. During the uptake phase, interindividual variability played a significant role in the predicted variation of acetone concentrations in blood, with variability up to a factor of 2-3 (90th/10th percentile ratio). After exposure ceased, the parameter uncertainty increased up to a factor of 100 after 16h, whereas variability remained unchanged. Parameter importance analysis indicated that variability in human physiology had the largest influence on predicted acetone concentrations in blood during exposure. Uncertainty in the metabolic rate of acetone was most important after the exposure had ceased and overruled variability.

Environmental impact assessment of pharmaceutical prescriptions: Does location matter?

A methodology was developed for the assessment and comparison of the environmental impact of two alternative pharmaceutical prescriptions. This methodology provides physicians with the opportunity to include environmental considerations in their choice of prescription. A case study with the two antibiotics ciprofloxacin and levofloxacin at three locations throughout Europe showed that the preference for a pharmaceutical might show spatial variation, i.e. comparison of two pharmaceuticals might yield different results when prescribed at different locations. This holds when the comparison is based on both the impact on the aquatic environment and the impact on human health. The relative impacts of ciprofloxacin and levofloxacin on human health were largely determined by the local handling of secondary sludge, agricultural disposal practices, the extent of secondary sewage treatment, and local food consumption patterns. The relative impacts of ciprofloxacin and levofloxacin on the aquatic environment were mostly explained by the presence of specific sewage treatment techniques, as effluents from sewage treatment plants (STPs) are the most relevant emission pathway for the aquatic environment.

The influence of uncertainty and location-specific conditions on the environmental prioritisation of human pharmaceuticals in Europe

The selection of priority APIs (Active Pharmaceutical Ingredients) can benefit from a spatially explicit approach, since an API might exceed the threshold of environmental concern in one location, while staying below that same threshold in another. However, such a spatially explicit approach is relatively data intensive and subject to parameter uncertainty due to limited data. This raises the question to what extent a spatially explicit approach for the environmental prioritisation of APIs remains worthwhile when accounting for uncertainty in parameter settings. We show here that the inclusion of spatially explicit information enables a more efficient environmental prioritisation of APIs in Europe, compared with a non-spatial EU-wide approach, also under uncertain conditions. In a case study with nine antibiotics, uncertainty distributions of the PAF (Potentially Affected Fraction) of aquatic species were calculated in 100∗100km(2) environmental grid cells throughout Europe, and used for the selection of priority APIs. Two APIs have median PAF values that exceed a threshold PAF of 1% in at least one environmental grid cell in Europe, i.e., oxytetracycline and erythromycin. At a tenfold lower threshold PAF (i.e., 0.1%), two additional APIs would be selected, i.e., cefuroxime and ciprofloxacin. However, in 94% of the environmental grid cells in Europe, no APIs exceed either of the thresholds. This illustrates the advantage of following a location-specific approach in the prioritisation of APIs. This added value remains when accounting for uncertainty in parameter settings, i.e., if the 95th percentile of the PAF instead of its median value is compared with the threshold. In 96% of the environmental grid cells, the location-specific approach still enables a reduction of the selection of priority APIs of at least 50%, compared with a EU-wide prioritisation.

Uncertainty and variability in human exposure limits – a chemical-specific approach for ciprofloxacin and methotrexate

Abstract Human exposure limits (HELs) for chemicals with a toxicological threshold are traditionally derived using default assessment factors that account for variations in exposure duration, species sensitivity and individual sensitivity. The present paper elaborates a probabilistic approach for human hazard characterization and the derivation of HELs. It extends the framework for evaluating and expressing uncertainty in hazard characterization recently proposed by WHO-IPCS, i.e. by the incorporation of chemical-specific data on human variability in toxicokinetics. The incorporation of human variability in toxicodynamics was based on the variation between adverse outcome pathways (AOPs). Furthermore, sources of interindividual variability and uncertainty are propagated separately throughout the derivation process. The outcome is a two-dimensional human dose distribution that quantifies the population fraction exceeding a pre-selected critical effect level with an estimate of the associated uncertainty. This enables policy makers to set separate standards for the fraction of the population to be protected and the confidence level of the assessment. The main sources of uncertainty in the human dose distribution can be identified in order to plan new research for reducing uncertainty. Additionally, the approach enables quantification of the relative risk for specific subpopulations. The approach is demonstrated for two pharmaceuticals, i.e. the antibiotic ciprofloxacin and the antineoplastic methotrexate. For both substances, the probabilistic HEL is mainly influenced by uncertainty originating from: (1) the point of departure (PoD), (2) extrapolation from sub-acute to chronic toxicity and (3) interspecies extrapolation. However, when assessing the tails of the two-dimensional human dose distributions, i.e. the section relevant for the derivation of human exposure limits, interindividual variability in toxicodynamics also becomes important.

Environmental impact of switching from the synthetic glucocorticoid prednisolone to the natural alkaloid berberine

Low amounts of human pharmaceuticals in the aquatic environment can affect bacteria, animals and ultimately humans. Here, the environmental consequences of a shift in prescription behavior from prednisolone to berberine was modeled using an environmental decision support system based on four consecutive steps: emission, fate, exposure and effect. This model estimates the relative aquatic and human health impacts of alternative pharmaceutical prescriptions throughout Europe. Since a Defined Daily Dose (DDD) of berberine has yet to be formulated, the environmental impacts of berberine and prednisolone were compared under the assumption of equal DDDs. Subsequently, the relative impact ratio indicates the extent to which the actual DDD of berberine might be higher to still be environmentally preferable over prednisolone. In fact, berberine can be administered at a six times higher dose throughout Europe before its impact on the aquatic environment exceeds that of one prescription of prednisolone. On average, the results for impacts on human health are similar, with the median impact ratio ranging between 5.87 and 22.8 depending on the level of drinking water purification. However, for some regions in Spain, Austria, Baltic States and Finland, berberine can only be considered an environmentally better alternative if it is administered at a lower dose than prednisolone. We conclude that for most regions in Europe it is, up until a certain dose of berberine, beneficial for the aquatic environment and therefore human health to prefer prescription of berberine over prednisolone.