Weijs, L

Weijs, Liesbeth

Institutional Repository Universiteit Antwerpen

Development of physiologically based pharmacokinetic models for the bioaccumulation of persistent organic pollutants in marine mammals

Open Marine Archive

Development o f physiologically based pharmacokinetic models for 
the bioaccumulation o f persistent organic pollutants in marine 
mammals
Weijs Liesbeth
Systemic Physiological and Ecotoxicological Research (SPHERE), Department o f Biology, University o f 
Antwerp, Groenenborgerlaan 171, 2020 Antwerpen, Belgium 
E-mail: liesbeth.weiis@uantwerpen.be
Factors, such as a greater demand fo r products and more sophisticated industrial techniques, have 
caused a growing number o f chemicals in the environment. Due to  a lack o f e ffic ient metabolic 
breakdown or e lim ination processes in organisms and in the environment, these chemicals can be 
passed on in the aquatic and terrestria l food webs leading to  higher levels in the predator compared 
to its prey. Marine mammals are apex predators in marine ecosystems and as such, they accumulate 
considerable amounts o f chemicals through the ir diet. Evidence in the literature has shown that 
these amounts can have a major negative impact on the ir immune, endocrine and reproductive 
system or even on the ir survival in general. Marine mammals do not seem to  have the appropriate 
enzyme systems to be able to  deal w ith chemicals. They experience the negative effects o f pollution 
themselves and at the same time, pass the chemicals on to the ir offspring. As a consequence, levels 
o f contaminants in these animals decrease only slowly even though the industria l production o f 
several chemicals has been restricted or banned in the past.
In order to  prevent repetitions o f past situations, it is im portant to  gain knowledge about the 
absorption, d is tribu tion  and elim ination o f known or ‘o ld ’ chemicals in marine mammals. 
Understanding the kinetics and effects o f old chemicals can be useful to assess the impact o f new 
chemicals w ith comparable properties compared to  the old ones before these new chemicals are 
being manufactured. From th is point o f view, studying known, old chemicals is undoubtedly useful 
fo r the risk assessment o f new compounds.
In th is thesis, the kinetics o f known or trad itional chemicals such as PCBs and PBDEs, was 
investigated in harbour porpoises and long-finned p ilo t whales by using physiologically based 
pharmacokinetic (PBPK) models. These computerized models combine physiological inform ation o f 
the organism o f interest and chemical properties o f the chemical o f interest to  reflect the kinetics o f 
that compound in the body o f the organism. Similar to  exposure experiments in which all factors 
are controlled to  m inimize the large degree o f variability, models fo r wild populations are also more 
reliable if the datasets used fo r evaluation o f the models are somewhat ‘ robust’ or ‘un ifo rm ’. For 
practical reasons, trends are easier to visualize and parameters are easier to estimate if the number 
o f interfering, external factors are reduced to a m inimum. For theoretical reasons, scattered data 
can lead to parameter estimates that are not reflecting the intrinsic, physiological capabilities o f the 
species.
Consequently, it was im portant to  investigate firs t which factors were influencing the levels of 
pollutants in the blood since blood is the only circulation medium in the models. Blood samples o f 
harbour seals and porpoises o f d ifferent health condition, orig in  (captivity versus wild), gender and 
age were analysed. Results showed that only emaciated animals had deviating concentrations and 
profiles o f PCBs and PBDEs in the ir blood compared to animals that were not emaciated. Of course, 
starvation can occur in wild populations, but is defin ite ly not common fo r all wild animals. The 
conclusion here was thus that datasets o f blood could be used in the bioaccumulation models. 
However, blood is never sampled at the same time as tissues in marine mammals. In m ulti- 
compartmental models as the ones developed in th is work, data o f more tissues was preferred to 
evaluate the model predictions fo r as much compartments as possible simultaneously.
Because the Black Sea harbour porpoise dataset was both restricted in time (animals were from  
1997-1998) and space (animals from  the Black Sea do not leave the Black Sea area), these results 
were preferably used to evaluate the very firs t prelim inary harbour porpoise model predictions. 
These models were developed to explain the bioaccumulation o f several PCB congeners (PCB 153, 
PC B 180, PCB 101, PCB 149, PCB 118, PCB 99, PCB 170) and PBDE congeners (PBDE 47, PBDE 99, 
PBDE 100 and PBDE 153) in male harbour porpoises. Model outputs showed that levels o f all PCBs 
and PBDEs reached high levels at the end o f lactation period (e.g. firs t year o f life) after which the 
growth d ilu tion  effect and a change in d iet caused a decline in concentrations followed by an 
increase in concentrations fo r the rest o f the lives o f the Black Sea harbour porpoises. The models
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were then applied to assess temporal trends by using the dataset o f harbour porpoises from  the 
North Sea. During th is modelling exercise, levels o f PCBs and PBDEs were found to  decrease from  
1990 until 2008, although not at the same rate fo r all PCB and PBDE congeners. For some PCB 
congeners, the PBPK models were also used to  test the metabolic biotransform ation capacity fo r PCB 
11 8, PCB 149 and PCB 101. Results suggested a fa irly  weak metabolic breakdown o f PCB 118 and 
an enhanced capacity fo r metabolic breakdown o f PCB 101 w ith higher age. In contrast, results were 
inconclusive about the metabolic capacities fo r PCB 149. So far, all attempts to estimate parameters 
were performed manually and the sensitivity o f the parameters on the model output was tested by a 
‘one-at-a-time’ or local sensitivity analysis. Flowever, th is type o f sensitivity analysis ignores 
potential correlations between the parameters. Flence, more statistically sound parameter 
estimation methods and global sensitivity tests that take into account potential interactions 
between the parameters were needed in order to  improve the robustness o f the models.
Applying new methods fo r parameter estimation and sensitivity analyses was, thus, the next step. 
So, in the most recent PBPK model fo r bioaccumulation o f pesticides (p ,p ’-DDT, p ,p ’-DDE, p ,p ’-DDD) 
in harbour porpoises, parameters were estimated using Bayes’ theorem executed w ith Markov chain 
Monte Carlo (MCMC) simulations. In addition, the influence o f changes in parameter values on the 
model output was tested using global sensitivity analyses. Compared to  all previous PBPK models, 
th is model fo r bioaccumulation o f pesticides differed not only in the statistical techniques, but also 
in its complexity. Whereas all previous models showed the kinetics o f a single compound, the 
pesticide model showed the kinetics o f p ,p ’-DDT and its two metabolites p ,p ’-DDE and p ,p ’-DDD at 
the same time ensuring a high connectivity between the kinetics o f these three compounds. Similar 
to the previous harbour porpoise models, the structural model was firs t evaluated using a dataset of 
harbour porpoises from  the Black Sea after which the parameter range estimates were fu rther 
optim ized using the dataset o f harbour porpoises from  the North Sea.
The same techniques (Bayesian PBPK modelling and MCMC simulations) were also used fo r a PBPK 
model fo r the lifetime bioaccumulation o f PCB 1 53 in long-finned pilo t whales. For th is species, two 
datasets were available from  two mass stranding events. Long-finned p ilo t whales have tig h t fam ily 
group bonds so whenever an individual ends up on the beach, all other members o f the group 
follow. For the animals, these mass strandings are traumatic, but they are a great opportun ity  fo r 
monitoring and modelling as a dataset cannot possibly be more ‘homogeneous’. In contrast to  the 
dataset o f the Black Sea harbour porpoises, only blubber samples were available fo r the long-finned 
p ilo t whales. The PBPK models fo r the bioaccumulation o f PCB 153 in p ilo t whales are therefore 
smaller than the models in harbour porpoises. Nevertheless, parameters were estimated w ith the 
most suitable technique fo r th is type o f models, making the p ilo t whale model already a useful 
fram ework fo r evaluating sim ilar or more elaborate datasets in the future.
This work provides new ideas and innovative approaches to study b iom onitoring data. The 
bioaccumulation models developed here can already be used as a fram ework to compare to  new 
datasets, but can also be fu rthe r optim ized and expanded in the future. These results are, 
therefore, not only a useful addition to  existing knowledge, but provide also new perspectives to 
assess pollution and its effects in marine mammals. Such an integrated approach is required to  set 
up guidelines fo r conservation o f a species. As a result, the models developed in th is work are 
undoubtedly useful tools fo r risk assessment purposes.
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Development of physiologically based pharmacokinetic models for the bioaccumulation of persistent organic pollutants in marine mammals

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