Toxicological Concepts for Safer Chemical Design

Voutchkova and colleagues²² have outlined an extensive framework for safer chemical design using multiple data and modeling resources. These types of data generation and modeling approaches are the basis of the process for a green chemistry model for specific series of chemicals used or proposed for use as reagents, solvents, or chemical intermediates in chemical synthesis. The simplified scheme involves a model building process, where chemical structures of interest are evaluated for chemical motifs (structural alerts) known to be associated with human health or environmental hazards, chemicals are clustered into hazard categories and specific high- or higher-throughput and targeted assays are identified for each hazard category. Analogue series directly applicable to the chemistry under evaluation are prepared or obtained and screened in the relevant assays. With homologous or structurally similar series, local chemical-toxicity models can be developed, validated and incorporated into the initial computational screening process. This general method can be applied to any specific hazard, any series of chemicals, and any assay methodology. Examples of hazard categories include carcinogenicity; reproductive and developmental; mutagenicity; neurotoxicity; endocrine disruption; cardiovascular; dermatotoxicity; digestive system toxicity; hematotoxicity; hepatotoxicity; immunotoxicity; muscular toxicity; nephrotoxicity; ocular toxicity; ototoxicity; respiratory toxicity; persistence in the environment; bioaccumulative in the environment; toxic to water organisms; water contaminant; and air pollutant. structural motif alert and expert predictions can be achieved using opentox,²³ an open access system used to predict potential hazards from chemical structures and known chemical motifs associated with human health and environmental endpoints, and Derek from Lhasa,²⁴ a rule-based expert system that de-convolutes a chemical structure into sub-structural fragments and addresses potential toxicity consistent with the above hazard categories. the software is also used to create specific local expert predictions from screening data. Meteor (lhasa) predicts potential metabolites and the metabolite structures can be used in Derek predictions. this type of inquiry is highly useful for establishing basic information for rank-ordering compounds, as in early candidate selection, and in the process of safer chemical synthesis. Multiple screening approaches have been used for evaluation of chemical toxicity using high-throughput technology and multiple assays. these include the United states environmental protection agency (EpA) toxCast program²⁵ where over 2000 chemicals have been evaluated in over 700 high-throughput assays. this is a section of the Tox21 testing program, a collaboration among EpA, the National Institutes of Health (№H), including the national Center for advancing translational sciences at the national toxicology program at the national Institute of environmental health sciences, and the United states Food and Drug administration. the Tox21 program involves high-throughput screening of more than 10 000 environmental chemicals and approved drugs using more than 100 assays. ап data are publicly available, as discussed later. Wink and colleagues²⁶ discuss a quantitative high-content imaging in vitro process to elucidate chemical interactions with cellular adaptive stress response pathways to gain a better insight into chemical toxicities at a phenotypic cellular level. the key to their reported technology is a panel of reporter cell lines to monitor multiple key nodes of the adaptive stress response pathways. Examples include cellular redox homeostasis, unfolded protein response, endoplasmic reticulum damage, inflammatory signaling, and DNA damage response. these assays hold the potential to be incorporated into multiple large-scale screens to evaluate health-related chemically-induced biological phenomena in drug research as well as hazard identification.