May 10, 2010 by David Taylor
Historically, society has evaluated chemicals using different systems developed on the basis of the use to which the substance was put. Thus we have seen systems developed in Europe to manage and control agrochemicals, biocides, pharmaceuticals, industrial chemicals and veterinary medicines. This differentiation has been logical, useful and largely successful since the primary objective was to protect the human health of the user, those in their immediate vicinity and the environment in which the activity was taking place.
However, we now face a different issue; the rapid advance in analytical science at the end of the 20th century has enabled us to detect substances at exceedingly low concentrations1, and this has demonstrated that any substance that human beings use is likely to leave residual quantities of it detectable in many parts of the environment. This means that in order to manage risks effectively we need to improve our knowledge of the potential impact of long term chronic exposure to very low concentrations.
For this purpose it is no longer sensible to differentiate substances on the basis of ‘use’, the exposure we are now concerned about is universal and ‘use’ is not directly related to chemical structure and therefore to toxicological impact. For example, pharmaceuticals are only differentiated from agrochemicals or industrial chemicals by the use to which they are put e.g. the rodenticide Warfarin is also widely used as a human medicine. Environmental risk assessment and management of these micropollutants thus needs a different paradigm, in which all substances are subjected to appropriate assessment according to their potential impact and overall exposure patterns, rather than their proposed use.
Subsequent management of substances, aimed at different uses, needs, as now, to be considered carefully since the risk benefit assessments will vary according to use, e.g. society may accept a higher environmental risk for a human pharmaceutical than for a plasticiser.
A recent publication (Hutchinson et.al. 2007) suggests a new basis for ecotoxicological assessment utilising the Mode of Action (MOA) approach originally proposed by Verhaar (1992)
“A widely used MOA approach initiated in the early 1990s is the Verhaar categorization system for predicting acutely toxic effect concentrations of organic environmental pollutants to fish (Verhaar et al, 1992). This scheme separates organic chemicals into four distinct classes that can be assigned a mode of action (MOA). These four classes are as follows: MOA1 – inert chemicals (baseline toxicity); MOA2 – less inert chemicals; MOA3 – reactive chemicals; and MOA4 – specifically acting chemicals. Inert chemicals are chemicals that are not reactive when considering overall acute effects and that do not interact with specific receptors in an organism. The MOA of such compounds in acute aquatic toxicity is called (lethal) narcosis. Less inert chemicals (MOA2) are slightly more toxic than predicted by baseline toxicity estimations. These chemicals often are characterised as compounds acting by a so called ‘polar narcosis’ mechanism and commonly can be identified as possessing hydrogen-bond donor acidity, such as phenols and anilines. Escher and Hermens (2002), suggested that MOA1 and MOA2 are probably the same based on the lethal membrane concentration. Reactive chemicals (MOA3) display an enhanced toxicity that is related to the phenomenon that these chemicals can react unselectively with certain chemical structures commonly found in biomolecules or can be metabolized into more toxic species. Specifically acting chemicals (MOA4) exhibit pharmacological and toxicological effects because of (specific) interactions with certain receptor molecules. For example, agrochemicals and pharmaceuticals typically have one of the following protein targets: (a) receptors, (b) ion channels, (c) enzymes, (d) transporters (Seiler, 2002; Rang et al, 2003). The Verhaar categorisation scheme does not include metals or other inorganic substances and ionisable organic substances.”
This seems to be a very sensible and logical way forward that could enable an intelligent testing strategy to be developed. However it depends heavily on the availability of information on the distribution of receptors in different species. There is little benefit in testing a substance categorised as MOA4 on a species which dose not have the appropriate receptor.
However the rapid expansion of receptor mapping (Gunnarsson et.al. 2008) begins to make this a practical possibility.
Escher BI, Hermens JLM. 2002. Modes of action in ecotoxicology: their role in body burdens, species sensitivity, QSARs, and mixture effects. Environ Sci Technol 36:4201-4217.
Gunnarson L. et.al. 2008, Evolutionary Conservation of Human Drug Targets in Organisms used for Environmental Risk Assessments Environ. Sci. Technol. 42, 5807–5813
Hutchinson T H. et.al. 2007, ECETOC Technical Report 102
Rang HP, Dale MM, Ritter JM, Moore PK. 2003. Pharmacology – 5th edition. Churchill Livingstone Edinburgh, UK, pp 797.
Seiler JP. 2002. Pharmacodynamic activity of drugs and ecotoxicology – can the two be connected? Toxicol Lett 131:105-115.
Verhaar HJM, van Leeuwen CJ, Hermens JLM. 1992. Classifying environmental pollutants. 1: Structure-activity relationships for prediction of aquatic toxicity. Chemosphere 25:471-491.
1 Analysts can currently detect concentrations as low as 1 in 10 -15, and it is likely that the even lower concentrations will be measurable in the next decade.