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Accurate hazard and risk assessment of contaminants of emerging concern challenges fundamental concepts and methods within environmental toxicology. Prominent among the contaminants of emerging concern today are active pharmaceutical ingredients (APIs) and, increasingly, nanoparticles (NPs). However, many, if not all, other categories of new and existing substances could, in theory, also become contaminants of emerging concern. The term does not necessarily imply that all contaminants of emerging concern are new, merely that improved analytical chemistry has allowed us to discover existing contaminants in the environment or that new properties associated with existing compounds are revealed and cause concern.

Within the area of chemicals, new policies with global implications push the frontier in our field of environmental chemistry and toxicology. These include the European Union's chemicals policy Registration, Evaluation, Authorisation and Restriction of Chemical substances (REACH; http://ec.europa.eu/enterprise/reach/reach/index_en.htm), the Strategic Approach to International Chemicals Management (SAICM; http://www.saicm.org/index.php?ql=h&content=home), and the Globally Harmonised System of Classification and Labelling of Chemicals (GHS; http://ec.europa.eu/enterprise/reach/ghs/index_en.htm), which could, de facto, replace risk assessment by hazard assessment with little or no consideration of exposures or probability of adverse effects in the environment. Further challenges facing environmental risk assessment in general were recently comprehensively investigated by a U.S. Environmental Protection Agency (U.S. EPA) Science Advisory Board [1].

The major challenges from contaminants of emerging concern relate to potency, reactivity, and their assumed interactions with biological systems. Strong parallels exist between APIs and NPs. The modes of action of APIs in nontarget organisms and NPs in general are largely unknown and thus subject to speculation. To enhance our understanding, we need to discriminate between toxicokinetics (adsorption, distribution, metabolism, and excretion), toxicodynamics (interaction with the receptor[s]), and the resulting biological and ecological consequences to the organism, population, or community. From a scientific perspective, modes of action probably need to be considered before mechanisms of action, with the understanding that modes of action are consequences of the biochemical mechanisms but expressed at higher levels of biological organization. This focus would also lend itself more readily to modeling, analyzing, and predicting mixture toxicity based on concentration addition, independent action, or both.

It is believed that the receptor-mediated toxicocodynamic properties of APIs may cause sublethal response in nontarget organisms with homologous receptors, and there is a general acceptance that some APIs may have large acute to chronic ratios (ACRs), especially regarding nonstandardized chronic endpoints. Estrogens, for example, are involved in a chain of amplification steps within the endocrine system along the hypothalamic-pituitary-gonadal axis of the organism, resulting in high potency. Measurement of estrogenic responses in wildlife has required the development of novel ecotoxicological tests and endpoints, such as induction of vitellogenin in fish. The ACRs for APIs are generally very uncertain because of a lack of publicly available chronic ecotoxicity data. Similarly, the myriad of specific properties associated with NPs suggest that they may interact with specific receptors; whether these interactions also follow internal amplification processes that trigger high ACRs is unknown. Moreover, the existence of hormesis in these substances is still being explored and may further complicate assessment and regulation of contaminants of emerging concern.

The U.S. EPA is currently considering revised aquatic life criteria for contaminants of emerging concern under the Clean Water Act, as demonstrated in a recent draft report. In this process, the U.S. EPA working group is focused on the potential receptors of APIs and NPs and the test systems to develop criteria and the need for refining chronic toxicity assessment. The U.S. EPA working group recognizes that some contaminants of emerging concern, such as APIs and NPs, are likely never to reach concentrations in the environment that may induce acute lethality and toxicity, except for scenarios of accidental releases or as mixtures. There is, however, concern that chronic effects may occur at environmentally realistic concentrations. This raises the question of the relevance of acute toxicity testing, an issue the European Medicines Agency in 2006 also raised in their guidelines for environmental risk assessment of APIs, requesting mandatory chronic toxicity assessment in accordance with Organization for Economic Cooperation and Development (OECD) guidelines for fish, daphnia, and algae. The U.S. EPA working group acknowledges that the aquatic life criteria test guidelines provide flexibility, when appropriate, to deviate from normal chronic test procedures and adapt the test conditions, suggesting that surrogates for traditional chronic toxicity endpoints such as suborganismal biomarkers and behavioral data can be used. The U.S. EPA Tox Cast (http://www.epa.gov/ncct/toxcast/) initiative will, in time, provide some suggestions regarding biomarkers and endpoints of potential relevance for alternative chronic endpoints.

In contrast, there is growing empirical evidence that, compared to most other chemicals, pharmaceuticals do not have an overrepresentation of specific and receptor-mediated acute mechanisms of action in nontarget organisms [2]. In standardized acute tests, roughly 70% of all pharmaceuticals with publicly available toxicity data act via narcosis [3,4]. It is questionable, however, if the findings of nonspecific narcotic mechanism of action under standardized conditions are accurate predictors of chronic responses. Implicitly, the conclusion of the current acute testing is that the lipid bilayer of the cell membrane is the important target and that proteins, receptor systems, and channels at the surface of the membrane are less important. For substances that act via receptor mechanisms common to target and nontarget species, effects in target organisms could guide the development of chronic testing methods [5].

Also lacking for chemicals of emerging concern is a framework for assessing ecological relevance in the context of risk management. What constitutes a relevant adverse effect must be understood. For example, it is debatable whether an up-regulation of genes is considered harmful and ecologically relevant from a regulatory perspective. The public and political demand for alternative methods of characterizing responses, such as in silico and in vitro, also complicates matters. Despite the validity and need for these systems, from a scientific point of view, it will likely widen the laboratory to field extrapolation gap if this diverts resources away from development of in vivo and in-community tests. For new test methods for nontraditional endpoints to be implemented in risk assessment and management, ecological relevance must be understood. We currently have survival-based mathematical models for community responses that have been calibrated in microcosm experiments and that can be used in the risk assessment or management context ([6]; http://www.regulations.gov/fdmspublic/component/main?main=DocumentDetail&o=09000064800b807f). However, we lack similar models that address other responses mediated by behavior, physiological, and developmental mechanisms. In this context, it is important to note that necessity and relevance are not only questions of science but are also highly political, driven by public opinion, and influenced by commercial interests. The question is how much time and patience will citizens and the natural environment afford us to effectively help solve the increasingly pressing demands of society with regard to contaminants of emerging concern? Will society replace risk assessment with hazard assessments based on extreme levels of precaution? Thus, although we should place more emphasis on developing testing methods for nontraditional endpoints for contaminants of emerging concern in chronic exposure scenarios and testing of mixtures, this must be done in concert with developing the tools to extrapolate these responses to the level of the population, community, and ecosystem with appropriate validation.

In conclusion, despite powerful chemical assessment tools and updated adaptive chemical management policies, it is too early to declare “mission accomplished” for the understanding and regulation of chemicals. The chronic, low level, mixture exposure of contaminants of emerging concern continues to challenge ecotoxicology.

Acknowledgements

  1. Top of page
  2. Acknowledgements
  3. REFERENCES

This editorial is the product of personal experience and was sparked by discussions during the recent SETAC-EU meeting in Warsaw with Derek Muir and Herb Ward. Further, we wish to acknowledge the SETAC Pharmaceuticals Advisory Group.

REFERENCES

  1. Top of page
  2. Acknowledgements
  3. REFERENCES
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