Polycyclic aromatic hydrocarbons (PAH) are ubiquitous in the environment, are present in the diet and are constituents of tobacco smoke. High concentrations of PAH can be found in some working places and in soils of actual or abandoned industrial sites. Due to their occurrence in many matrices they enter the body by different pathways including dermal absorption, inhalation and ingestion. PAH are of considerable toxicological interest, because some of them are carcinogenic in laboratory animals and are obviously involved in chemically induced lung and colon cancers in humans.
In industrial areas, soils can be heavily polluted with PAH and, thus, can represent a potential health risk for the human population. We have particularly examined the effects of oral intake of PAH-contaminated soils by two animal models, rats and minipigs, by means of exposure biomarkers. Additionally, the toxicity of soils for microorganisms has been determined by common methods used to assess the risk potential of soils.

PAH modulate the expression profile of cytochromes P450 (CYP). In particular, CYP1A1 and CYP1B1 have been shown to be suitable exposure biomarkers for PAH in animals as well as humans (Roos et al., 1996, Arch. Environ. Contam. Toxicol. 30, 107-113, Lemm et al., Int J Hyg Environ Health 207, 325–335). As an indication of PAH bioavailability upon oral intake of contaminated soils, induction of CYP1A1 in various organs of rats and minipigs is observed. Induction is seen in the duodenum as the organ of contaminant entry and in the liver as the organ with highest capacity for PAH metabolism. Additionally, increased CYP1A1-levels are found in lung, kidney and spleen after oral soil intake indicating that contaminants escape the primary duodenal and hepatic metabolism and reach further organs. Interestingly, the tissue-related CYP1A1 induction pattern differs between rats and minipigs (Roos et al., in press, Xenobiotica). In the rat, CYP1A1 induction is low in the duodenum and high in the liver, while in minipigs induction is high in the duodenum and lower in the liver. This finding is important for the selection of the animal model used for extrapolations to humans. However, the human response pattern is not known as yet. Generally, CYP1A1 induction does not correlate with results of toxicity tests with lower organisms performed with the same soils. For this discrepancy, the organic carbon content of the soil is largely responsible. It severely affects the bioavailability of soil bound PAH for microorganisms, but obviously affects the mobilization efficiency for PAH in the gastro-intestinal tract of mammals to a minor extent only. Soil remediation by different methods may result in a significant reduction of the PAH content and of toxicity determined by microorganism assays. However, ingestion of remediated soils by rats shows that the induction potential for CYP1A1 is only slightly decreased after remediation (Roos et al., 2004, Toxicology 205, 181 – 194). This means that the major inducing components, PAH with 5 or 6 aromatic rings, resist biological remediation or soil washing and remain in the soil. Dose response relationships underline the preferential contribution of this PAH subclass to CYP1A1 induction. Based on known exposure conditions and scenarios for children playing on contaminated sites, the dose response relationships found in animal models also reveal that induction effects are to be expected in these children. In summary, cytochromes P450, in particular CYP1A1, are suitable biomarkers to assess the bioavailability of soil bound contaminants and their effects on mammalian species. However, there are a number of questions to be answered with respect to the extrapolation of animal data to humans such as the identification of the suitable animal model.

Environmental chemicals may exert toxicity towards different organisms and through a variety of mechanisms. With respect to organic substances, a current paradigm of aquatic toxicology is that every chemical is at least as toxic as would be expected from its potential for hydrophobic membrane irritation. The latter is often called baseline toxicity or narcosis and can be modeled with simple quantitative structure-activity relationships (QSARs), using the octanol/water partition coefficient (Kow) as only molecular descriptor. More specific interactions with endogeneous compounds typically increase the toxicity as compared to narcosis. Here, computational chemistry provides a useful tool to quantify biochemically relevant reactivity patterns, which allow a systematic analysis of experimental toxicity results in terms of underlying mechanisms as well as relevant features of the molecular and electronic structure of the compounds. Besides predicting toxic effect levels, calculated molecular properties may also serve to classify chemical substances in terms of prevalent modes of toxic action. An example of the latter is the discrimination between baseline and excess toxicity, which offers a new way to lay down test priorities also in the regulatory context. The approach is illustrated with different compound classes, biological species and toxic endpoints.

Key words: Molecular Toxicology, Mode of Action, Computational Chemistry, QSAR,
Hazard Assessment

For risk estimations in toxicology the dose response relations are of utmost importance especially in the low dose range in cases when the effects of an toxic agent can be best described by a linear no threshold (LNT) model. For ionising radiation and certain genotoxic chemicals the LNT model is assumed for genetic and carcinogenic effects although a solid scientific proof is not possible. However, there are other carcinogenic chemicals for which the LNT model is very uncertain or even a threshold in the dose effect curve is very plausible. It arises the question to which degree there exist similarities or dissimilarities between the mechanisms of those toxic agents for which the assumption of the LNT model appears reasonable. The development of cancer is a multistep process in which mutations and changes of cell proliferation are dominating and DNA is the main target molecule in the initiative events.
Ionising radiation can interact with DNA directly, the following DNA damage frequently occurs in clusters whereas genotoxic chemicals generally react with DNA in an isolated monomolecular fashion especially in the low exposure range. Furthermore chemicals have quite often to be activated through metabolic processes in order to develop genotoxic activities. Metabolic events are also involved in the inactivation and distribution of such drugs between organs and cells in a mammalian organism. Thus there exist characteristic differences between the actions of ionising radiation and chemicals with respect to these first steps of carcinogenesis which lead to the malignant cell transformation. After the interaction of the toxic principles with DNA quite a number of modifying processes like DNA repair and apoptosis can interfere with the further processing of the DNA damage which show similar features for the consequences of ionising radiation and of chemicals.
The later steps in cancer development which are connected to promotion and progression are very similar or even appear to be identical for the causation of cancer by ionising radiation or by chemicals. The most important biological mechanisms are changes in cell proliferation in these stages. These processes can be modified by a number of endogenous processes like hormonal factors as well as by chemicals. Therefore combined exposures of toxic agents may interfere in these stages of cancer development. Also genetic predispositions may make individuals more susceptible for cancer causation against ionising radiation as well as against chemicals.
Exposures to ionising radiation or chemicals may lead to specific patterns of cancers, however, the observed cancers do not differ with respect to their clinical appearance as well as to molecular or cellular features. These cancers also cannot be differentiated from “spontaneous” cancers which may have developed from endogenous processes. The background of these “spontaneous” cancers shows a considerable spread due to gender, age, lifestyle etc. Therefore it is not possible in the low exposure range to analyse an eventual increase of cancers. The quantitative risk can only be obtained by extrapolation under these circumstances.

Reference: C. Streffer, H. Bolt, D. Follesdal, P.Hall, J.G. Hengstler, P. Jakob,
D. Oughton, K. Prieß, E. Rehbinder, E. Swaton: Low Dose Exposures in the Environment – Dose-Effect Relations and Risk Evluation. Springer Berlin-Heidelberg-New York-Hong Kong-London-Milan-Paris-Tokyo, 2004.
 

The objective of exposure characterization of contaminated groundwater in the environmental risk assessment is to measure or model exposure in terms of routes, intensity, exposure media, spatial scales and time scales. The exposure characterization requires among others the evaluation of data quality and relevance for risk assessment, the identification and quantification of sources and emissions as well as the distribution pathways of distinct groundwater flow directions. Major aim is to convert the conceptual model to a quantitative one and predict the transport and fate of contaminants in the ground water in a regional scale. The latter includes the importance of hydraulic transport, the transformation and mainly biodegradation of organic compounds, as well as the distribution pathways. One of the important aspects of exposure characterization in the field of environmental geology and hydrogeology is the process of natural attenuation of organic chemicals. These include the natural processes of the spread of contamination and reduce of concentration and amount of pollutants at contaminated sites by biodegradation, chemical degradation, dispersion, sorption, and volatilization.

Large scale groundwater contamination sites like the Bitterfeld-Wolfen industrial region in the eastern part of Germany is characterized by different environmental impacts caused by the former chemical industry and extensive landscape devastation by lignite mining for more than 100 years. Due to the multi-source regional contamination in the Quaternary and Tertiary aquifers characterized by more than 180 different organic substances, a risk assessment and management of the regional contaminated sites have to be developed. Due to the recently changing regional hydraulic conditions and resulting distribution pathways in near future, a re-assessment of the environmental risks and resulting land use management approach is needed.

Therefore, a GIS-based spatial model of the area has been built, which includes the following major topics: digital 3-D model of the subsurface geology, groundwater monitoring data of contaminants, hydrogeological data and actual land-use management as well as protection areas. Identification, assessment and remediation of a large-scale groundwater contamination require a detailed knowledge of the geological structure to predict the fate-and-pathway conditions of contaminants in the subsurface. Within the SAFIRA-project, a model sector of the Bitterfeld/Wolfen area was chosen to transfer the structural geological data of the Tertiary and Quaternary aquifer units into a digital geological model. An assignment of hydraulic parameters to individual sedimentary bodies allows a combination with flow and transport models to predict the exposure routes in the aquifers. Future exposure estimates are used to provide decision-makers with an understanding of potential future exposures and threats and include a qualitative estimate of the likelihood of such exposures occurring. One of the objectives of the ongoing research of the mega site Bitterfeld are the assessment of pathway-specific intakes for current and future exposures to individual substances for human and aquatic organisms. Therefore, a specific contamination profile for this region was derived on the base of available monitoring data within the project.

Prof. Dr. Peter Wycisk, Environmental Geology
Managing Director University Center of Environmental Sciences UZU
Institute of Geological Sciences, Martin Luther University, Von Seckendorff Platz 3,
D-06120 Halle / Saale, Germany