- Email: [email protected]
Environmental contaminants and target organ toxicities – new insights into old problems
Toxicology Letters 230 (2014) 81–84
Contents lists available at ScienceDirect
Toxicology Letters journal homepage: www.elsevier.com/locate/toxlet
Editorial
Environmental contaminants and target organ toxicities – new insights into old problems
Environmental contaminants comprise an extremely diverse group of natural and synthetic substances present in soil, air and water that can cause harmful effects in human populations or biological ecosystems. They may be introduced into the environment as a consequence of human activities such as agriculture, industrial production, burning of fossil fuels or wastewater discharge. Natural sources include release of air pollutants from volcanoes, biological decay and forest fires as well as metal contamination of ground water. The possible effects on human health or ecosystems from environmental contaminants are as diverse as the substances themselves, and the ever-increasing number of scientific studies on this subject is perhaps only matched by the increasing level of public concern. Making sense of an avalanche of often conflicting data requires going back to the first principle of toxicology: the dose makes the poison. In the case of environmental contaminants this requires an understanding of the toxicity or hazardous properties of the substance or mixture as well as an assessment of its environmental persistence and potential to bioaccumulate. The current issue contains a series of 17 research articles and 11 reviews that aim to dissect the various aspects of biological effects encountered during exposure to environmental contaminants. The articles focus on the assessment of potentially hazardous substances and their impact on the development of adverse outcomes and diseases. In addition, evidence from in in vivo and in vitro models presenting the molecular mechanisms that lead to the development of toxicity and disease from exposure to environmental contaminants is presented. Emphasis is given to specific endpoints and biomarkers which can be used to assess the potential risk and toxicity caused by environmental contaminants in vivo. Human epidemiological studies which aim to clarify the associations between exposure to environmental contaminants and specific health effects are also included. Pesticides are one of the most widely studied groups of environmental contaminants. They differ from other chemicals in that their purpose is to display biological activity (similar to pharmaceuticals), hence they would be expected to have (side)effects on non-target organisms. As a consequence, they have a rich toxicological and ecotoxicological database because their authorization for use requires a formal risk assessment. Nevertheless, there is concern over potential human and environmental effects of pesticides, particularly upon long-term exposure to low levels, which may not be picked up in standard regulatory hazard testing schemes. One such example is the possible link between pesticides http://dx.doi.org/10.1016/j.toxlet.2014.08.003 0378-4274/ ã 2014 Elsevier Ireland Ltd. All rights reserved.
and neurodegenerative diseases (Baltazar et al., 2014). Although there is both experimental and epidemiological evidence for a link, so far no specific substance has been unequivocally shown to be causing a specific neurodegenerative outcome at typical environmental concentrations. Organophosphate chemicals are specific neurotoxins and concern has therefore been expressed over possible effects on the developing human brain. González-Alzaga et al. (2013) systematically reviewed the epidemiological literature on this subject and concluded that there is some evidence that prenatal exposure, in particular, may contribute to neurodevelopmental and behavioural deficits in children. However, due to the large variability in study design and methodologies, no firm conclusions could be drawn, prompting the authors to call for more standardized methodologies for future studies. The in vitro study by Campanha et al. (2014) provides some evidence that organophosphates can interfere with acetylcholinesterase trophic function during critical periods of strong cell adhesion and differentiation, while Benabent et al. (2014) found a previously unrecognized effect of organophosphates on additional esterases in soluble chicken brain fractions. Apart from their known neurotoxic effects, organophosphates and other insecticides are suspected of other non-target effects which are of concern for human health. Michalakis et al. (2013) found high concentrations of dialkyl phosphate metabolites as well as organochlorine pesticides in hair samples of children with hypospadias and their parents compared to the general population and even to occupationally exposed workers. Pesticide effects on the male reproductive system were also the subject of the review by Mehrpour et al. (2014) who found highly variable results with regard to sperm quality, calling once again for well-designed longterm studies which take into account the potential multifactorial origins of male infertility. With regard to cancer risk, Parrón et al. (2013) using an ecological study design, found that the prevalence rates of cancer at most organ sites were significantly higher in Andalusian districts with high pesticide use. Costa et al. (2014) compared biomarkers of exposure, early effects and susceptibility in groups of conventional and organic farmers, and found that those farmers using pesticides had an increase in micronuclei and chromosomal aberrations, indicating a higher risk of genotoxicity. Both these studies are hypothesis-forming and the results need to be confirmed in other research studies. The elucidation of mechanisms of neurotoxic damage by pesticides and biocides are the subject of two in vitro studies. Chantong et al. (2014) used a mouse BV-2 cell model to highlight
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the potential role of oxidative stress and pro-inflammatory cytokine markers in microglia cells in the development of dibutyltin-induced CNS damage. Neuroinflammation was also the subject of the investigation by Sandström von Tobel et al. (2014) who showed in a three-dimensional whole rat brain cell culture model that neurons partially recovered from early paraquat exposure whereas astrogliosis persisted, accompanied by delayed microglial activation which may induce further neurodegeneration. Neurotoxicity is also a feature of acute selenium intoxication, but possible nervous system effects of chronic exposure are much less well characterized. Vinceti et al. (2013) concluded from their review of experimental and epidemiological studies that there is a plausible mechanistic basis for neurotoxicity from long-term exposure and that the relatively few human studies looking at neurotoxicity endpoints have demonstrated non-specific symptoms such as lethargy, dizziness, paraesthesia and an excess incidence of amyotrophic lateral sclerosis. However, the evidence is limited due to methodological problems, so again, more wellcontrolled specific human studies are necessary. Potential wildlife effects of persistent organic pollutants were investigated in carp by Karaca et al. (2014) and in waterbirds by Kocagöz et al. (2014) CYP1A and antioxidant activities in carp liver were substantially higher in areas with higher organochlorine pollution. In waterbirds, activities of antioxidant enzymes were correlated with liver concentrations of several organochlorines. The presence of polyhalogenated chemicals in the environment has long been of concern due to their activity in biological systems, their persistence and ability to bioaccumulate. While many of the chlorinated chemicals such as PCBs and several polychlorinated pesticides have been banned or phased out, others such as the dioxins will continue to enter the environment as by-products of industrial activities or through natural processes such as forest fires. Sorg (2013) has reviewed the evidence for AhR activation as the main source of the toxicological properties of dioxins. Using the induction of chloracne as an example, he points out that certain AhR agonists found in vegetables do not cause this condition, whereas other chemicals and therapeutic agents may induce a chloracne-like syndrome without activating AhR. Jeanneret et al. (2013) analysed urine samples from a cohort of workers who were industrially exposed to high doses of dioxin in the 1960s. They focused on steroid metabolites and bile acids as potential biomarkers of long-term dioxin effects using an untargeted metabolomics approach. The analysis was guided by comparison with the urinary metabolic patterns related to the extreme phenotype represented by the dioxin poisoning of the former Ukrainian president Victor Yushchenko. In recent years, other groups of halogenated compounds have become the focus of attention, in particular perfluorinated chemicals (PFCs) and polybrominated diphenyl ethers (PBDEs). One of the important knowledge gaps relates to the tissue burden of these chemicals. Fàbrega et al. (2014) tested a PBPK model for predicting PFOS and PFOA levels in blood and human tissue samples. While the model predicted blood levels well, this was not the case for tissue levels, showing the need for further and more detailed biological monitoring of these compounds. Endocrine disruption and immunotoxicity are among the possible adverse effects ascribed to PFCs. In a rat model, Pereiro et al. (2014) found that PFOS induced an inhibition of the hypothalamicpituitary-adrenal axis activity at different levels, thereby altering corticosterone secretion. In addition, some morphological changes were seen in adrenal zona fasciculata cells. With regard to immunotoxicity, Corsini et al. (2014) reviewed recent experimental and epidemiological evidence and found that effects were seen in animal studies at dose levels comparable to those reported in highly exposed human populations and wildlife. Given that there is
potential for bioaccumulation and exposure to multiple PFCs, they concluded that there was a risk of immunosuppressive effects in humans, particularly in the case of prenatal exposure. Two reviews focus on the potential neurodevelopmental and neurobehavioural effects of PFCs and PBDEs. Roth and Wilks (2014) carried out a systematic review of recent epidemiological studies using a checklist-type quality assessment scheme. Methodological discrepancies were frequent, and associations with adverse neurodevelopmental and neurobehavioural outcomes were highly variable. Collectively, the data did not support a strong causal link with PBDE and PFC exposure, but they raise questions which should be explored in hypothesis-driven studies using harmonized methodologies and detailed exposure assessments. The mechanistic basis for possible neurodevelopmental effects of PBDEs is the subject of the review by Costa et al. (2013); they highlighted in particular two possible non-mutually exclusive modes of action. One could be the interaction with thyroid hormone homeostasis at different levels with an indirect effect on the developing brain. Alternatively or additionally, PBDEs may directly affect nerve cells through oxidative damage and interference with signal transduction and neurotransmitters. Benzo[a]pyrene (BaP) is a ubiquitous environmental contaminant and known human carcinogen found in, amongst others, cigarette smoke, diesel exhaust, coal tar and grilled foods. BaP was used in the study by Androutsopoulos and Tsatsakis (2013) to induce CYP1 enzymes in an in vitro system. This led to an enhanced cytostatic effect caused by the flavonoid eupatorin-5-methyl (E5M) upon MCF7 breast cancer cells which offers a novel mechanism of action of CYP1 enzymes involving enhancement of the antitumor properties of E5M in cells exposed to CYP1 inducers. Two studies looked at the effects of prenatally administered BaP, one on adiposity in mice, and one on hyperoxic lung injury in rats. Ortiz et al. (2013) found that prenatal exposure to BaP increased visceral adiposity and caused hepatic steatosis in wild type female mice whereas GSH-deficient mice were resistant to these effects; this resistance was associated with hepatic downregulation of several genes involved in lipid biosynthesis and upregulation of antioxidant genes. Thakur et al. (2014) found an increased susceptibility of newborn rats to oxygen-mediated lung injury and alveolar simplification following maternal exposure to BaP, suggesting that modulation of CYP1A/1B1 enzymes, increases in oxidative stress, and BaP–DNA adducts contributed to this adverse outcome. Bolognesi and Moretto (2013) reviewed exposure and biomonitoring data from studies carried out in the rubber manufacturing industry and concluded that a genotoxic hazard existed in certain plants, but the data are inadequate to estimate the genotoxic risk associated with the exposure in different manufacturing processes. They called for further studies addressing the genotoxicity of the exposure mixtures in the different production phases and processes of rubber manufacturing industries in order to refine exposure control and preventive measures. There is an increasing need to develop reliable and costeffective alternatives to the present battery of regulatory toxicity tests. Sogorb et al. (2014) have developed a step-wise approach to embryotoxicity and developmental toxicity testing. The first level would focus on short-term cellular assays to detect effects in early differentiation stages. The second level would involve longer-term cellular embryotoxicity tests to identify embryotoxicants that have an effect on late differentiation stages. The third stage would consider tests with whole zebrafish embryos because they allow the determination of hazards based on molecular and morphological alterations. The selected papers in this issue emphasize the major impact that environmental contaminants may have on human and ecosystem health and highlight the increasing need for effective and integrated
[(Fig._1)TD$IG]
M.F. Wilks, A.M. Tsatsakis / Toxicology Letters 230 (2014) 81–84
83
Fig. 1. The web of interactions highlighting the challenge of linking diseases with exposures.
approaches to risk assessment and exposure evaluation in human populations and biological ecosystems. This is a non-trivial task which requires a shift in our approach to toxicity testing for regulatory purposes. Most of the research articles in this special issue use non-standard methods for the hazard identification of environmental contaminants. Risk assessors often have difficulties using such data which are generated under specific experimental conditions that may be difficult to reproduce. As a consequence, important research findings may be ignored until such time as further confirmatory evidence becomes available. A way forward may be the application of integrated frameworks for testing such as the OECD’s adverse outcome pathway (AOP) approach. Using bisphenol A as an example, FitzGerald and Wilks (2014) argue that such an approach is needed to help researchers in designing relevant studies, and risk assessors in evaluating them. The same difficulty applies to the use of information from epidemiology studies, prompting many of the authors of the review papers in this issue to call for more harmonization in study methodologies, more systematic handling of potential confounders, and a better characterization of exposure. The complex issue of linking exposures to diseases/health effects can be summarized under the term “web of interactions” (Fig. 1). Three important issues contribute to the complexity of the research task: the first refers to the big number and categories of diseases and/or disorders (e.g. neurological, pulmonary, skin diseases, etc.) that can be involved. The second is related to the expanding number of measurable exposures to specific substances or categories of pollutants (e.g. pesticides, industrial chemicals, natural toxins, endocrine disruptors etc.). The third issue is associated with the effect of various types of confounders (e.g. sex, age, habits, socioeconomic status, medical history etc.) on both exposure and disease manifestation. Using database-derived terminology, the type of problems and interactions can be described as a many-to-many relationship. In most of the cases, the direct pollutant-disease interaction has not been studied due to the enormous number of possible pairs. Otherwise, the result could be “no”, “weak” or “strong” evidence of interaction. Often, a weak evidence report may be followed by controversial results (e.g. of no or strong evidence) of interaction from other studies. There is a long list of issues that can lead to
controversies (e.g. hidden effects from other pollutants, unknown or not studied confounders, issues of chemical analysis, misclassification of exposure or disease, variability in response etc.), however, better design and reporting of adequately powered, hypothesisdriven studies would go a long way to address these controversies. Finally, although most of the articles are concerned with human health effects, it should be emphasized that humans are but one species in the ecosystem. There is perhaps no other area in toxicology where human and ecological risk assessment can learn as much from each other as in the evaluation of the risks of environmental contaminants. We sincerely appreciate the contributions by all authors and gratefully acknowledge the reviewers of the submitted manuscripts. We would also like to thank the editor-in-chief, Wolfgang Dekant, the journal publisher Meghan Jendrysik, the journal manager Farheen Fathima, publishing content specialist Arthi Prianka and production manager Paul Crabtree for their encouragement and continuous support throughout the process.
References Androutsopoulos, V.P., Tsatsakis, A.M., 2014. Benzo[a]pyrene sensitizes MCF7 breast cancer cells to induction of G1 arrest by the natural flavonoid eupatorin-5methyl ether, via activation of cell signaling proteins and CYP 1-mediated metabolism. Toxicol. Lett. 230, 304–313. Baltazar, M.T., Dinis-Oliveira, R.J., de Lourdes Bastos, M., Tsatsakis, A.M., Duarte, J.A., Carvalho, F., 2014. Pesticides exposure as etiological factors of Parkinson’s disease and other neurodegenerative diseases – a mechanistic approach. Toxicol. Lett. 230, 85–103. Benabent, M., Vilanova, E., Mangas, I., Sogorb, M.A., Estévez, J., 2014. Interaction between substrates suggests a relationship between organophosphorussensitive phenylvalerate- and acetylcholine-hydrolyzing activities in chicken brain. Toxicol. Lett. 230, 132–138. Bolognesi, C., Moretto, A., 2014. Genotoxic risk in rubber manufacturing industry: a systematic review. Toxicol. Lett. 230, 345–355. Campanha, H.M., Carvalho, F., Schlosser, P.M., 2014. Active and peripheral anionic sites of acetylcholinesterase have differential modulation effects on cell proliferation, adhesion and neuritogenesis in the NG108-15 cell line. Toxicol. Lett. 230, 122–131. Chantong, B., Kratschmar, D.V., Lister, A., Odermatt, A., 2014. Dibutyltin promotes oxidative stress and increases inflammatory mediators in BV-2 microglia cells. Toxicol. Lett. 230, 177–187. Corsini, E., Luebke, R.W., Germolec, D.R., Dewitt, J.C., 2014. Perfluorinated compounds: emerging POPs with potential immunotoxicity. Toxicol. Lett. 230, 263–270.
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Costa, L.G., de Laat, R., Tagliaferri, S., Pellacani, C., 2014. A mechanistic view of polybrominated diphenyl ether (PBDE) developmental neurotoxicity. Toxicol. Lett. 230, 282–294. Costa, C., García-Lestón, J., Costa, S., Coelho, P., Silva, S., Pingarilho, M., Valdiglesias, V., Mattei, F., Dall’armi, V., Bonassi, S., Laffon, B., Snawder, J., Teixeira, J.P., 2014. Is organic farming safer to farmers’ health? A comparison between organic and traditional farming Toxicol. Lett. 230, 166–176. Fàbrega, F., Kumar, V., Schuhmacher, M., Domingo, J.L., Nadal, M., 2014. PBPK modeling for PFOS and PFOA: validation with human experimental data. Toxicol. Lett. 230, 244–251. FitzGerald, R.E., Wilks, M.F., 2014. Bisphenol A – why an adverse outcome pathway framework needs to be applied. Toxicol. Lett. 230, 368–374. González-Alzaga, B., Lacasaña, M., Aguilar-Garduño, C., Rodríguez-Barranco, M., Ballester, F., Rebagliato, M., Hernández, A.F., 2014. A systematic review of neurodevelopmental effects of prenatal and postnatal organophosphate pesticide exposure. Toxicol. Lett. 230, 104–121. Jeanneret, F., Boccard, J., Badoud, F., Sorg, O., Tonoli, D., Pelclova, D., Vlckova, S., Rutledge, D.N., Samer, C.F., Hochstrasser, D., Saurat, J.H., Rudaz, S., 2014. Human urinary biomarkers of dioxin exposure: analysis by metabolomics and biologically-driven data dimensionality reduction. Toxicol. Lett. 230, 234–243. Karaca, M., Varışlı, L., Korkmaz, K., Ozaydın, O., Perçin, F., Orhan, H., 2014. Organochlorine pesticides and antioxidant enzymes are inversely correlated with liver enzyme gene expression in Cyprinus carpio. Toxicol. Lett. 230, 198– 207. daş, B., Sıkı, M., Orhan, H., 2014. Environmental Kocagöz, R., Onmuş, O., Onat, I., Cag and biological monitoring of persistent organic pollutants in waterbirds by noninvasive versus invasive sampling. Toxicol. Lett. 230, 208–217. Mehrpour, O., Karrari, P., Zamani, N., Tsatsakis, A.M., Abdollahi, M., 2014. Occupational exposure to pesticides and consequences on male semen and fertility: a review. Toxicol. Lett. 230, 146–156. Michalakis, M., Tzatzarakis, M.N., Kovatsi, L., Alegakis, A.K., Tsakalof, A.K., Heretis, I., Tsatsakis, A., 2014. Hypospadias in offspring is associated with chronic exposure of parents to organophosphate and organochlorine pesticides. Toxicol. Lett. 230, 139–145. Ortiz, L., Nakamura B1, Li, X., Blumberg, B., Luderer, U., 2014. Reprint of “In utero exposure to benzo[a]pyrene increases adiposity and causes hepatic steatosis in female mice, and glutathione deficiency is protective”. Toxicol. Lett. 230, 314– 321. Parrón, T., Requena, M., Hernández, A.F., Alarcón, R., 2014. Environmental exposure to pesticides and cancer risk in multiple human organ systems. Toxicol. Lett 230, 157–165.
Pereiro, N., Moyano, R., Blanco, A., Lafuente, A., 2014. Regulation of corticosterone secretion is modified by PFOS exposure at different levels of the hypothalamic– pituitary–adrenal axis in adult male rats. Toxicol. Lett. 230, 252–262. Roth, N., Wilks, M.F., 2014. Neurodevelopmental and neurobehavioural effects of polybrominated and perfluorinated chemicals: a systematic review of the epidemiological literature using a quality assessment scheme. Toxicol. Lett. 230, 271–281. Sandström von Tobel, J., Zoia, D., Althaus, J., Antinori, P., Mermoud, J., Pak, H.S., Scherl, A., Monnet-Tschudi, F., 2014. Immediate and delayed effects of subchronic Paraquat exposure during an early differentiation stage in 3D-rat brain cell cultures. Toxicol. Lett. 230, 188–197. Sogorb, M.A., Pamies, D., de Lapuente, J., Estevan, C., Estévez, J., Vilanova, E., 2014. An integrated approach for detecting embryotoxicity and developmental toxicity of environmental contaminants using in vitro alternative methods. Toxicol. Lett. 230, 356–367. Sorg, O., 2014. AhR signalling and dioxin toxicity. Toxicol. Lett. 230, 225–233. Thakur, V.S., Liang, Y.W., Lingappan, K., Jiang, W., Wang, L., Barrios, R., Zhou, G., Guntupalli, B., Shivanna, B., Maturu, P., Welty, S.E., Moorthy, B., Couroucli, X.I., 2014. Increased susceptibility to hyperoxic lung injury and alveolar simplification in newborn rats by prenatal administration of benzo[a]pyrene. Toxicol. Lett. 230, 322–332. Vinceti, M., Mandrioli, J., Borella, P., Michalke, B., Tsatsakis, A., Finkelstein, Y., 2014. Selenium neurotoxicity in humans: bridging laboratory and epidemiologic studies. Toxicol. Lett. 230, 295–303.
Martin F. Wilks* Aristidis M. Tsatsakis Swiss Centre for Applied Human Toxicology, University of Basel, Klingelbergstrasse 61, 4056 Basel, Switzerland Department of Forensic Sciences & Toxicology, Medical School, University of Crete, Heraklion 71409, Greece * Corresponding author. E-mail address: [email protected] (M. Wilks). Available online 7 August 2014
Contents lists available at ScienceDirect
Toxicology Letters journal homepage: www.elsevier.com/locate/toxlet
Editorial
Environmental contaminants and target organ toxicities – new insights into old problems
Environmental contaminants comprise an extremely diverse group of natural and synthetic substances present in soil, air and water that can cause harmful effects in human populations or biological ecosystems. They may be introduced into the environment as a consequence of human activities such as agriculture, industrial production, burning of fossil fuels or wastewater discharge. Natural sources include release of air pollutants from volcanoes, biological decay and forest fires as well as metal contamination of ground water. The possible effects on human health or ecosystems from environmental contaminants are as diverse as the substances themselves, and the ever-increasing number of scientific studies on this subject is perhaps only matched by the increasing level of public concern. Making sense of an avalanche of often conflicting data requires going back to the first principle of toxicology: the dose makes the poison. In the case of environmental contaminants this requires an understanding of the toxicity or hazardous properties of the substance or mixture as well as an assessment of its environmental persistence and potential to bioaccumulate. The current issue contains a series of 17 research articles and 11 reviews that aim to dissect the various aspects of biological effects encountered during exposure to environmental contaminants. The articles focus on the assessment of potentially hazardous substances and their impact on the development of adverse outcomes and diseases. In addition, evidence from in in vivo and in vitro models presenting the molecular mechanisms that lead to the development of toxicity and disease from exposure to environmental contaminants is presented. Emphasis is given to specific endpoints and biomarkers which can be used to assess the potential risk and toxicity caused by environmental contaminants in vivo. Human epidemiological studies which aim to clarify the associations between exposure to environmental contaminants and specific health effects are also included. Pesticides are one of the most widely studied groups of environmental contaminants. They differ from other chemicals in that their purpose is to display biological activity (similar to pharmaceuticals), hence they would be expected to have (side)effects on non-target organisms. As a consequence, they have a rich toxicological and ecotoxicological database because their authorization for use requires a formal risk assessment. Nevertheless, there is concern over potential human and environmental effects of pesticides, particularly upon long-term exposure to low levels, which may not be picked up in standard regulatory hazard testing schemes. One such example is the possible link between pesticides http://dx.doi.org/10.1016/j.toxlet.2014.08.003 0378-4274/ ã 2014 Elsevier Ireland Ltd. All rights reserved.
and neurodegenerative diseases (Baltazar et al., 2014). Although there is both experimental and epidemiological evidence for a link, so far no specific substance has been unequivocally shown to be causing a specific neurodegenerative outcome at typical environmental concentrations. Organophosphate chemicals are specific neurotoxins and concern has therefore been expressed over possible effects on the developing human brain. González-Alzaga et al. (2013) systematically reviewed the epidemiological literature on this subject and concluded that there is some evidence that prenatal exposure, in particular, may contribute to neurodevelopmental and behavioural deficits in children. However, due to the large variability in study design and methodologies, no firm conclusions could be drawn, prompting the authors to call for more standardized methodologies for future studies. The in vitro study by Campanha et al. (2014) provides some evidence that organophosphates can interfere with acetylcholinesterase trophic function during critical periods of strong cell adhesion and differentiation, while Benabent et al. (2014) found a previously unrecognized effect of organophosphates on additional esterases in soluble chicken brain fractions. Apart from their known neurotoxic effects, organophosphates and other insecticides are suspected of other non-target effects which are of concern for human health. Michalakis et al. (2013) found high concentrations of dialkyl phosphate metabolites as well as organochlorine pesticides in hair samples of children with hypospadias and their parents compared to the general population and even to occupationally exposed workers. Pesticide effects on the male reproductive system were also the subject of the review by Mehrpour et al. (2014) who found highly variable results with regard to sperm quality, calling once again for well-designed longterm studies which take into account the potential multifactorial origins of male infertility. With regard to cancer risk, Parrón et al. (2013) using an ecological study design, found that the prevalence rates of cancer at most organ sites were significantly higher in Andalusian districts with high pesticide use. Costa et al. (2014) compared biomarkers of exposure, early effects and susceptibility in groups of conventional and organic farmers, and found that those farmers using pesticides had an increase in micronuclei and chromosomal aberrations, indicating a higher risk of genotoxicity. Both these studies are hypothesis-forming and the results need to be confirmed in other research studies. The elucidation of mechanisms of neurotoxic damage by pesticides and biocides are the subject of two in vitro studies. Chantong et al. (2014) used a mouse BV-2 cell model to highlight
82
M.F. Wilks, A.M. Tsatsakis / Toxicology Letters 230 (2014) 81–84
the potential role of oxidative stress and pro-inflammatory cytokine markers in microglia cells in the development of dibutyltin-induced CNS damage. Neuroinflammation was also the subject of the investigation by Sandström von Tobel et al. (2014) who showed in a three-dimensional whole rat brain cell culture model that neurons partially recovered from early paraquat exposure whereas astrogliosis persisted, accompanied by delayed microglial activation which may induce further neurodegeneration. Neurotoxicity is also a feature of acute selenium intoxication, but possible nervous system effects of chronic exposure are much less well characterized. Vinceti et al. (2013) concluded from their review of experimental and epidemiological studies that there is a plausible mechanistic basis for neurotoxicity from long-term exposure and that the relatively few human studies looking at neurotoxicity endpoints have demonstrated non-specific symptoms such as lethargy, dizziness, paraesthesia and an excess incidence of amyotrophic lateral sclerosis. However, the evidence is limited due to methodological problems, so again, more wellcontrolled specific human studies are necessary. Potential wildlife effects of persistent organic pollutants were investigated in carp by Karaca et al. (2014) and in waterbirds by Kocagöz et al. (2014) CYP1A and antioxidant activities in carp liver were substantially higher in areas with higher organochlorine pollution. In waterbirds, activities of antioxidant enzymes were correlated with liver concentrations of several organochlorines. The presence of polyhalogenated chemicals in the environment has long been of concern due to their activity in biological systems, their persistence and ability to bioaccumulate. While many of the chlorinated chemicals such as PCBs and several polychlorinated pesticides have been banned or phased out, others such as the dioxins will continue to enter the environment as by-products of industrial activities or through natural processes such as forest fires. Sorg (2013) has reviewed the evidence for AhR activation as the main source of the toxicological properties of dioxins. Using the induction of chloracne as an example, he points out that certain AhR agonists found in vegetables do not cause this condition, whereas other chemicals and therapeutic agents may induce a chloracne-like syndrome without activating AhR. Jeanneret et al. (2013) analysed urine samples from a cohort of workers who were industrially exposed to high doses of dioxin in the 1960s. They focused on steroid metabolites and bile acids as potential biomarkers of long-term dioxin effects using an untargeted metabolomics approach. The analysis was guided by comparison with the urinary metabolic patterns related to the extreme phenotype represented by the dioxin poisoning of the former Ukrainian president Victor Yushchenko. In recent years, other groups of halogenated compounds have become the focus of attention, in particular perfluorinated chemicals (PFCs) and polybrominated diphenyl ethers (PBDEs). One of the important knowledge gaps relates to the tissue burden of these chemicals. Fàbrega et al. (2014) tested a PBPK model for predicting PFOS and PFOA levels in blood and human tissue samples. While the model predicted blood levels well, this was not the case for tissue levels, showing the need for further and more detailed biological monitoring of these compounds. Endocrine disruption and immunotoxicity are among the possible adverse effects ascribed to PFCs. In a rat model, Pereiro et al. (2014) found that PFOS induced an inhibition of the hypothalamicpituitary-adrenal axis activity at different levels, thereby altering corticosterone secretion. In addition, some morphological changes were seen in adrenal zona fasciculata cells. With regard to immunotoxicity, Corsini et al. (2014) reviewed recent experimental and epidemiological evidence and found that effects were seen in animal studies at dose levels comparable to those reported in highly exposed human populations and wildlife. Given that there is
potential for bioaccumulation and exposure to multiple PFCs, they concluded that there was a risk of immunosuppressive effects in humans, particularly in the case of prenatal exposure. Two reviews focus on the potential neurodevelopmental and neurobehavioural effects of PFCs and PBDEs. Roth and Wilks (2014) carried out a systematic review of recent epidemiological studies using a checklist-type quality assessment scheme. Methodological discrepancies were frequent, and associations with adverse neurodevelopmental and neurobehavioural outcomes were highly variable. Collectively, the data did not support a strong causal link with PBDE and PFC exposure, but they raise questions which should be explored in hypothesis-driven studies using harmonized methodologies and detailed exposure assessments. The mechanistic basis for possible neurodevelopmental effects of PBDEs is the subject of the review by Costa et al. (2013); they highlighted in particular two possible non-mutually exclusive modes of action. One could be the interaction with thyroid hormone homeostasis at different levels with an indirect effect on the developing brain. Alternatively or additionally, PBDEs may directly affect nerve cells through oxidative damage and interference with signal transduction and neurotransmitters. Benzo[a]pyrene (BaP) is a ubiquitous environmental contaminant and known human carcinogen found in, amongst others, cigarette smoke, diesel exhaust, coal tar and grilled foods. BaP was used in the study by Androutsopoulos and Tsatsakis (2013) to induce CYP1 enzymes in an in vitro system. This led to an enhanced cytostatic effect caused by the flavonoid eupatorin-5-methyl (E5M) upon MCF7 breast cancer cells which offers a novel mechanism of action of CYP1 enzymes involving enhancement of the antitumor properties of E5M in cells exposed to CYP1 inducers. Two studies looked at the effects of prenatally administered BaP, one on adiposity in mice, and one on hyperoxic lung injury in rats. Ortiz et al. (2013) found that prenatal exposure to BaP increased visceral adiposity and caused hepatic steatosis in wild type female mice whereas GSH-deficient mice were resistant to these effects; this resistance was associated with hepatic downregulation of several genes involved in lipid biosynthesis and upregulation of antioxidant genes. Thakur et al. (2014) found an increased susceptibility of newborn rats to oxygen-mediated lung injury and alveolar simplification following maternal exposure to BaP, suggesting that modulation of CYP1A/1B1 enzymes, increases in oxidative stress, and BaP–DNA adducts contributed to this adverse outcome. Bolognesi and Moretto (2013) reviewed exposure and biomonitoring data from studies carried out in the rubber manufacturing industry and concluded that a genotoxic hazard existed in certain plants, but the data are inadequate to estimate the genotoxic risk associated with the exposure in different manufacturing processes. They called for further studies addressing the genotoxicity of the exposure mixtures in the different production phases and processes of rubber manufacturing industries in order to refine exposure control and preventive measures. There is an increasing need to develop reliable and costeffective alternatives to the present battery of regulatory toxicity tests. Sogorb et al. (2014) have developed a step-wise approach to embryotoxicity and developmental toxicity testing. The first level would focus on short-term cellular assays to detect effects in early differentiation stages. The second level would involve longer-term cellular embryotoxicity tests to identify embryotoxicants that have an effect on late differentiation stages. The third stage would consider tests with whole zebrafish embryos because they allow the determination of hazards based on molecular and morphological alterations. The selected papers in this issue emphasize the major impact that environmental contaminants may have on human and ecosystem health and highlight the increasing need for effective and integrated
[(Fig._1)TD$IG]
M.F. Wilks, A.M. Tsatsakis / Toxicology Letters 230 (2014) 81–84
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Fig. 1. The web of interactions highlighting the challenge of linking diseases with exposures.
approaches to risk assessment and exposure evaluation in human populations and biological ecosystems. This is a non-trivial task which requires a shift in our approach to toxicity testing for regulatory purposes. Most of the research articles in this special issue use non-standard methods for the hazard identification of environmental contaminants. Risk assessors often have difficulties using such data which are generated under specific experimental conditions that may be difficult to reproduce. As a consequence, important research findings may be ignored until such time as further confirmatory evidence becomes available. A way forward may be the application of integrated frameworks for testing such as the OECD’s adverse outcome pathway (AOP) approach. Using bisphenol A as an example, FitzGerald and Wilks (2014) argue that such an approach is needed to help researchers in designing relevant studies, and risk assessors in evaluating them. The same difficulty applies to the use of information from epidemiology studies, prompting many of the authors of the review papers in this issue to call for more harmonization in study methodologies, more systematic handling of potential confounders, and a better characterization of exposure. The complex issue of linking exposures to diseases/health effects can be summarized under the term “web of interactions” (Fig. 1). Three important issues contribute to the complexity of the research task: the first refers to the big number and categories of diseases and/or disorders (e.g. neurological, pulmonary, skin diseases, etc.) that can be involved. The second is related to the expanding number of measurable exposures to specific substances or categories of pollutants (e.g. pesticides, industrial chemicals, natural toxins, endocrine disruptors etc.). The third issue is associated with the effect of various types of confounders (e.g. sex, age, habits, socioeconomic status, medical history etc.) on both exposure and disease manifestation. Using database-derived terminology, the type of problems and interactions can be described as a many-to-many relationship. In most of the cases, the direct pollutant-disease interaction has not been studied due to the enormous number of possible pairs. Otherwise, the result could be “no”, “weak” or “strong” evidence of interaction. Often, a weak evidence report may be followed by controversial results (e.g. of no or strong evidence) of interaction from other studies. There is a long list of issues that can lead to
controversies (e.g. hidden effects from other pollutants, unknown or not studied confounders, issues of chemical analysis, misclassification of exposure or disease, variability in response etc.), however, better design and reporting of adequately powered, hypothesisdriven studies would go a long way to address these controversies. Finally, although most of the articles are concerned with human health effects, it should be emphasized that humans are but one species in the ecosystem. There is perhaps no other area in toxicology where human and ecological risk assessment can learn as much from each other as in the evaluation of the risks of environmental contaminants. We sincerely appreciate the contributions by all authors and gratefully acknowledge the reviewers of the submitted manuscripts. We would also like to thank the editor-in-chief, Wolfgang Dekant, the journal publisher Meghan Jendrysik, the journal manager Farheen Fathima, publishing content specialist Arthi Prianka and production manager Paul Crabtree for their encouragement and continuous support throughout the process.
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Martin F. Wilks* Aristidis M. Tsatsakis Swiss Centre for Applied Human Toxicology, University of Basel, Klingelbergstrasse 61, 4056 Basel, Switzerland Department of Forensic Sciences & Toxicology, Medical School, University of Crete, Heraklion 71409, Greece * Corresponding author. E-mail address: [email protected] (M. Wilks). Available online 7 August 2014