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In addition, the adverse outcomes of in vitro tests can be compared with different levels of biological organization that are of regulatory relevance, which may reduce the need or reliance of live animal testing. However, the current level of detail of AOPs are mostly narrative and not quantitative, thus there is a need to move to more molecularly defined mechanisms, for which the term pathway of toxicity PoT has been coined [ 43 ], in order to allow for modelling.

With PoTs, mechanism-based read-across studies will be feasible if all receptors within a potential pathway are examined in biological testing. AOPs and PoTs will have major implications for the advancement of predictive toxicology, an important tool which would improve Green Toxicology approaches in developing and designing safer chemicals.

An understanding of the molecular structure, functionality and adverse outcomes associated with chemicals is essential in aiding in the benign-by-design concept. In vitro assays are typically rapid, with high-throughput and large data output that can be reliably reproducible and cost effective. These qualities are particularly important for the safety and hazard assessment of new products, which can result in substantial costs for failures and problems detected late in the development and regulatory testing phase.

In addition, many in vitro methods produce mechanism-specific data, which is another important aspect that can aid with the design of alternative compounds with lesser toxicity. With newer and more innovative in vitro tests, the focus moves more towards chronic exposures at low concentrations on cells and organ systems rather than the traditional adverse effects observed in in vivo animal tests that are often conducted at high doses.

Furthermore, the results of in vitro testing e. IC 50 values in enzyme or receptor assays could be used to develop predictive in silico tools. With the availability of such computational methods, chemists can test and screen their new structures for warnings, and learn to avoid the synthesis of toxic compounds at earlier stages of development.

Toxicology

As such, the development of in vitro methods complement and may eventually reduce the essential use of in vivo studies, which directly supports the principles of Green Toxicology. Thus, with the addition of any new in vitro method for eco toxicity testing we will get one step closer towards an integrated process of gaining early toxicological information and adapting substance synthesis, leading to the efficient development of green chemicals and products with reduce toxicity.

The new approaches and scientific advances in molecular, cellular and computational toxicology can lead to a better application of predictive toxicology in the manufacturing of new materials and chemicals, which directly supports Green Toxicology. Predictive toxicology aims to develop new and innovative non-animal tests that do not simply duplicate existing animal tests but also provide a new scientific basis for product development and safety testing.

Hence, the objective of such an application is to complement and extend traditional toxicity testing through a better understanding of toxicity pathways that contribute to products that are safer for humans and the environment. The incorporation and consideration of toxic potential and outcomes early in the design phase is an essential component of Green Toxicology and requires collaboration among chemists, toxicologists, industry, and regulators. Alternatives to current mandatory testing protocols are likely to influence future regulatory policy in Europe. However, if these new tools and methods for product development and risk assessment are to become widely accepted, then policy makers and regulators need to be informed and persuaded of the benefits of these alternative approaches and applications.

Additional lessons for Green Toxicology can be learned from past product development and production through the application of the precautionary principle [ 17 , 18 ]. The precautionary principle is applied in situations when harm to either the environment or human life does not need to be conclusively proven in order for risk to be addressed through discretionary decisions and policies. In this respect, Green Toxicology can incorporate the precautionary principle by limiting the suspect or potential adverse toxicological consequences during the discovery, development and production of safer and more sustainable products.

As such, knowledge about the previous selection of occupational, public health and environmental hazards can be examined to determine if further or earlier measures could have been employed to prevent harm e. Although often neglected, the precautionary principle offers many lessons and improvements that can be of use to developing products that are less harmful and should be a main driving force behind not only Green Toxicology but also Green Chemistry.

Environmental Health

Traditionally, the development of alternative testing methods in Europe was largely driven by ethical rationales such that studies were targeted for their use of many animals, or for their high potential to result in pain and suffering e. Therefore, the currently validated in vitro assays particularly apply to the aforementioned endpoints [ 45 , 46 ]. In the following paragraphs, a brief overview is provided concerning the 3Rs method currently employed at BASF, which are used within a screening context to avoid the development of compounds with an unfavourable hazard profile i.

The traditional in vivo Draize irritation test for skin and eyes, in which a restrained, conscious animal is exposed dermal and ocular, respectively to a test substance for a set amount of time to determine toxicological effects, has long since been criticized for the limitations in species differences, subjective scoring, and experimental variability.

The replacement of the Draize test for skin irritation was historically one of the first steps towards the full replacement of animal testing. These tests are employed within the context of a simple testing strategy described elsewhere [ 47 — 50 ]. In brief, a test substance is applied topically to a reconstructed human epidermis RhE that closely mimics the biochemical and physiological properties of the upper parts of the human skin using human derived non-transformed keratinocytes as cell sources. The indication of corrosive and irritant test substances is determined by their ability to decease cell viability cytotoxicity below defined threshold levels as measured via the MTT-assay.

For eye irritation, the situation is essentially quite similar. The replacement of the Draize test for eye irritation again was achieved by two methods. The BCOP and similar ex vivo tests utilize slaughterhouse material to assess the severe eye irritation potential of a test substance through its ability to induce opacity and increased permeability in, for example, an isolated bovine cornea.

In contrast, the EIT and similar tests use the commercially available reconstructed human cornea-like epithelium RhCE , which closely mimics the histological, morphological, biochemical and physiological properties of the human corneal epithelium to determine if a test substance is an eye irritant based on its ability to induce cytotoxicity in RhCE tissue, as measured by the MTT assay.

These tests, and alternatives, are again used within the context of a simple testing strategy and described in further detail elsewhere [ 52 — 56 ]. Skin sensitization is a process more complex than skin or eye irritation, and includes several key events such as 1 dermal penetration, 2 protein reactivity, 3 inducing stress responses in keratinocytes, 4 activation of immune cells dendritic cells in the skin, and 5 their translocation to the lymph nodes.

Given this complexity, it is difficult to imagine one single test that would be able to incorporate all of these steps [ 57 ]. Therefore, the development of an in vitro testing approach for skin sensitization resulted in the best solution [ 58 ], consisting of three assays addressing hazard identification according to the abovementioned key events 2—4. With this testing strategy, a correlation with human skin sensitizers is obtained, which is slightly better than that obtained in the local lymph node assay LLNA [ 66 , 67 ].

The endpoint of systemic toxicity has not been of major interest to chemical companies and regulatory bodies. With good intention, it was proposed to use the results of cytotoxicity testing to determine the starting dose for acute oral toxicity testing. However, it should be noted here that good intention is not always a good guidance. Such expert knowledge was determined from information about the substance class or comparable formulation. Thus, Green Toxicology, which utilizes and considers all available information about a test substance through, for example, Q SAR, read-across and grouping of substances approaches may lead to reductions in the amount of chemicals and animals required for testing and development of new substances.

To screen for compounds with endocrine effects, two in vitro systems are often used that address the most common causes for endocrine activity: 1 agonist or antagonist effects on the androgen receptor AR or estrogen receptor ER and 2 interference with steroid synthesis. There are a variety of in vitro, wildlife and mammalian screen tests available to screen for endocrine disruptor activity, with details on each provided elsewhere [ 69 ].

Activation and deactivation of either receptor are monitored by the change in colour of a dye sensitive to the activity of the enzyme.

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If deemed necessary, a follow-up is carried out at later stages of testing for endocrine activity with a refined or day study in which a blood metabolome analysis is included. Additional testing strategies for endocrine testing have been reported elsewhere [ 70 , 71 ]. Another important aspect of systemic toxicity, with respect to avoidance of chemicals, with a problematic hazard profile is neurotoxicity.

In this assay, primary neurons are grown on chips connected with a device that measures the spontaneous firing of the neurons. Compounds that stimulate or attenuate neuronal activity can be monitored by the changes in the firing rates of the neurons [ 74 , 75 ]. The last, and possibly the most important endpoint in toxicology, which has been investigated in screening strategies, is the toxic effects on development.


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It should be noted here that relatively little is unfortunately known about the modes of action involved in developmental toxicity, in comparison with many endpoints in systemic toxicity such as neurotoxicity, endocrine effects or carcinogenicity. Therefore, mode of action-based screens are not readily available. Two more holistic approaches are used to assess developmental toxicity: 1 the chick embryotoxicity screening test CHEST [ 76 ] and 2 the fish embryo toxicity FET test [ 77 , 78 ].


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In both assays, the development of a complete embryo is monitored and evaluated during certain embryonic and foetal stages. As such, these tests are very close to being animal studies but are not considered as such because of the very early timing of testing and the absence of a maternal organism being exposed. A third test for assessing developmental toxicity is the mouse embryonic stem cell test EST; [ 79 — 81 ]. Nevertheless, with the inclusion of additional endpoints, such as placental transfer which can be measured in vitro , reasonable prediction values can be obtained for certain classes of chemicals [ 82 ].

However, it is clear that a better understanding of AOPs in developmental toxicity will be necessary to develop a series of targeted in vitro assays to entail better screening for this very important endpoint.

SKIN AS A BARRIER

With new omics technologies becoming more readily available, we are now at a point where there is a chance to tackle complex toxicological concerns, such as systemic toxicity. Following the successful development of a metabolomics based approach to predict systemic toxicity from a single drop of blood from short-term toxicity studies [ 83 ], the potential of this technology using an in vitro approach is being explored. A proof of principle was achieved using fibroblast to assess the effects of compounds on cell energy metabolism [ 84 ].

This work was followed by intensive research to establish an in vitro system combining liver cells and metabolomics for the identification of liver toxicity and modes of action. It has been observed that identification of liver toxicity can indeed be achieved by in vitro metabolomics using the HepG2 liver cell line.

Research using cells from other organs is continuing; striving for the identification of organ-specific toxicity. The final goal would be to have a full array of cell systems to reliably predict systemic toxicity [ 85 ]. It is essential that work to obtain such alternative methods be continued because their availability is needed to reduce animal use, reduce the use and production of waste, and to increase the utility of such methods in chemical screening regulation. With this available, only a few grams of compound would be needed to evaluate systemic toxicity, and to move ahead one step further in the development of Green Chemistry with Green Toxicological methods.

Finally, with the availability of sufficient data on, for example, compound—receptor interactions, it is possible to create mathematical models which can assign a likelihood that a particular chemical structure will interact with a biological target. The process of developing such models is not necessarily fast and depends very much on the quality of the input data.

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However, the availability of such models will help chemists to design new compounds that perform the desired task and have a higher likelihood of a favourable toxicological profile. Safety-by-design will result in a win—win situation, with less animal testing and intrinsically safer products. In contrast to household and consumer chemicals, where the optimization process of the properties during product development is often independent of the safety assessment, the drug development process can be seen as a series of iterative steps to optimize efficacy and simultaneously lower the safety as early as possible.

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Therefore, the early assessment of toxicity before the first application to man clinical phase 1 plays a pivotal role in this process. Compounds for which the preclinical toxicological assessment identifies an adverse effect profile that exceeds the expected benefit for the patient will be excluded from progression in the development pipeline.

Preclinical toxicology is hereby facing two challenges: on the one hand, the predictivity of the applied toxicological assays should be improved on a continuous basis to avoid false predictions both false positives and false negatives , while on the other hand, the predictions should be made as early as possible during the process of drug candidate selection. This early assessment causes a shift from in vivo to in vitro to in silico methods. Some toxicological effects can in the meantime be predicted based on in silico methods with reasonable reliability, such as mutagenicity, phospholipidosis, and to a lesser extent skin sensitization [ 86 ].

It can be foreseen that integrated testing strategies will evolve with the advent of AOPs and a better understanding of the mechanisms of toxicological effects, which comprise a combination of in silico and in vitro tools to predict toxicological effects. For example, models that predict pharmacokinetic behaviour absorption, distribution of compounds based on physicochemical properties could be combined with predictions of liver transport based on QSAR transporter models.

The inclusion of subsequent results from in vitro toxicity assays with hepatocytes or mitochondria will help to identify compounds that have a propensity towards drug-induced liver toxicity DILI. Such complementary tools may limit and remove the most problematic candidates in early phases or allow medicinal chemistry departments to optimize the structure early on. Triggered by numerous publications on occurrence of pharmaceuticals in the environment, the European Commission was asked to deliver a strategic approach to pollution of water by pharmaceutical substances.

The corresponding report was published in [ 87 ]. Despite these straightforward claims, the advances in the field of Green Toxicology for environmental safety are less evident than for human safety. The reason for this deficit is an inherent conflict of objectives during the optimization phase of a drug candidate, which is often overlooked in the discussion. One key criterion for low human toxicity is the partial stability of a drug candidate both with regard to human metabolism, as well as chemical stability towards light and temperature.

Unless we consider a so-called pro-drug, which requires metabolic activation for achieving efficacy, an otherwise unstable compound usually undergoes attrition during the drug development. Degradation or rapid metabolism of a drug candidate usually results in a lower exposure to the efficacious compound leading to a lower efficacy of disease treatment. This lower efficacy could only be overcome by increasing the dose, which in turn could result in an increased risk of side effects.

In addition, particular phase I metabolites or breakdown products may elicit adverse effects on their own, which can lower the therapeutic window. Striving for optimization of drug stability may result in the persistence of the drug after excretion and in sewage treatment in the aquatic environment. For some drugs, the concentrations reported in certain aquatic environments raise the concern of causing harm to environmental species.

As a matter of fact, the vast majority of active pharmaceutical ingredients show no ready biodegradability when subjected to the pertinent OECD screening tests for ready biodegradability [ 88 ].