a toxic substance is a small molecule , peptide , or protein that is capable of causing injury or death .
toxins , both natural and man - made , represent an important class of poisonous compounds that are ubiquitous in nature , in homes and in the workplace .
common toxins include pollutants , pesticides , preservatives , drugs , venoms , food toxins , cosmetic toxins , dyes and cleaning compounds .
indeed , common toxins are so ubiquitous that most adults will have been exposed to or will have 
while the concentration of most toxins in adults is generally below hazardous levels , their ubiquity essentially makes them an integral part of the human metabolome ( 1 ) .
this fact , combined with the recent advances in chemical detection technologies for monitoring low abundance compounds , has greatly increased the need to identify , quantify , classify and understand these common toxins ( 2 ) .
though a great deal of information has been acquired about toxic substances and their mechanism of action over the past 100 years , much of this information tends to be highly dispersed and of limited accessibility  often being confined to specialized textbooks , obscure government documents or subscription - requiring scientific journals .
a number of excellent , web - accessible toxic substance databases have started to appear , such as the animal toxin database ( atdb ) ( 3 ) , supertoxic ( 4 ) , aggregated computational toxicology resource ( actor ) ( 5 ) and the comparative toxicogenomics database ( ctd ) ( 6 ) .
in particular , actor and supertoxic provide bioassy data and chemical structure information for a very large number of industrial or pharmaceutically interesting chemicals ( > 60 000 for supertoxic , > 500 000 for actor ) .
atdb with 3844 peptide toxins and ctd with 5056 chemicals are somewhat more specialized , offering data on channel targets ( atdb ) or chemical - gene interactions ( ctd ) for a much smaller number of better - understood toxins .
each of these databases addresses the needs of certain communities such as animal physiologists ( atdb ) , toxicogenomics specialists ( ctd ) , environmental or industrial regulators ( actor ) or medicinal chemists interested in toxicity prediction ( supertoxic ) .
however , compared to a number of other widely used biochemical or metabolomic databases such as human metabolome database ( hmdb ) ( 1 ) , drugbank ( 7 ) or pharmgkb ( 8) most of today s online toxin or toxic compound databases are relatively lightly annotated , with fewer than 10 data fields per compound .
furthermore , the data model adopted by many databases seems to be focused on providing a little information about everything ( including somewhat exotic or extremely rare compounds ) at the expense of including a lot of information about those toxins that nearly everyone encounters .
consequently it is difficult to find answers to common questions such as : how does this poison work ?
what enzymes , receptors or organs does this toxin target ? where is this chemical found ? how does this toxin get into the body ?
how can i treat someone who has been exposed to this substance ? where can i find more information about this chemical ?
in other words , the information contained in these resources does not fully address the needs of physicians , toxicologists , clinical chemists , metabolomics researchers , educators and the general public .
indeed , members of these communities typically need in - depth , biological , chemical and mechanistic information about clinically relevant or commonly encountered toxins . in an effort to address these needs
t3db is a multi - purpose , freely available , online toxicology resource that provides in - depth , quantitative and molecular - scale information about toxins and their associated targets . in terms of its layout , content and depth of coverage , the t3db
is modeled closely after two other cheminformatic or metabolomics resources previously developed in our laboratory : the hmdb and drugbank .
as the name indicates , the t3db is primarily intended to be a database that links toxins with their biological ( usually protein ) targets .
this molecular interaction information is further supplemented with detailed descriptions of the toxin 's ; mechanism of action , its metabolism in the human body , its lethal or toxic dose levels , its potential carcinogenicity , exposure sources , symptoms or health effects and suggested treatment options . in total
each toxin listed in t3db contains more than 80 data fields covering the structure , chemistry , physico - chemical properties , toxicology , route of delivery , treatment and target protein / macromolecule properties .
t3db currently contains over 2900 toxin entries corresponding to more than 34 000 different synonyms .
these toxins are further connected to some 1300 protein targets through almost 33 500 toxin and toxin - target bonds which , in turn , are supported by more than 3100 references .
the entire database , including text , sequence , structure and image data , occupies nearly 16 gigabytes of data  most of which can be freely downloaded . 

table 1.summary of the data fields or data types found in each toxcardtoxin and medical informationtoxin target 
protein/ enzyme informationcommon namenamecompound typemechanism of action ( in humans)descriptiondescriptionsynonyms / iupac namesynonymschemical formulagene namechemical structureprotein sequencecas registry numbernumber of residuesinchi identifiermolecular weightpubchem compound idtheoretical pikegg compound idgo classificationuniprot idgeneral functionomim idpathwayschebi idreactionsbiocyc idsignalssupertoxic idtransmembrane regionsctd idessentialitystitch iddomain functiondrugbank idgenbank i d proteinpdb iduniprotkb idactor idcellular locationwikipedia linkgene sequencemonoisotopic massgenbank gene idmol filegenecard idpdb filegenatlas idsmileshgnc idappearancechromosome locationmelting pointlocusboiling pointsnpsdensitygeneral referencessolubilitypredicted logpspecific gravityflash pointvapour pressureroute of exposuremechanism of actionmetabolismtoxicity values ( experimental ld50s and lc50s)lethal dose ( for humans)carcinogenicity ( iarc classification)uses / sourcesminimum risk levelhealth effectssymptomstreatmentgeneral referencesprotein targets summary of the data fields or data types found in each toxcard the diversity of data types , required breadth of knowledge and widespread nature of the required data made the assembly of the t3db both difficult and time - consuming .
the t3db represents the accumulation of both qualitative and quantitative information derived from a variety of sources , including scientific journals , government records , chemical safety documents ( i.e. msds or material safety data sheets ) , textbooks , encyclopedias , online protein and protein structure databases , on - line metabolomic databases , electronic drug and pharmaceutical databases as well as existing toxin and toxicology databases . to compile , confirm and validate this comprehensive collection of data , more than a dozen toxicology , pharmacology and biochemistry textbooks , several thousands journal articles , nearly 20 different electronic databases , and at least 20 in - house or web - based programs were individually searched , accessed , compared , written , or run over the course of the past year .
the team of t3db contributors and annotators consisted of eight bioinformaticians with dual training in computing science and molecular biology / chemistry .
the t3db is designed to be a fully searchable web resource with many built - in tools and features for viewing , sorting and extracting toxin and toxin - target annotation , including structures and gene and protein sequences . a screenshot montage illustrating the types of viewing and searching options available is shown in figure 1 .
detailed instructions on where to locate and how to use these browsing / search tools are provided on the t3db homepage . as with any web - enabled database ,
the t3db supports standard text queries through the text search box located on the home page .
it also offers general database browsing using the  browse  button located in the t3db navigation bar . to facilitate browsing ,
the t3db is divided into synoptic summary tables which , in turn , are linked to more detailed 
all of the t3db s summary tables can be rapidly browsed , sorted or reformatted in a manner similar to the way pubmed abstracts may be viewed .
clicking on the toxcard button found in the leftmost column of any given t3db summary table opens a webpage describing the toxin of interest in much greater detail .
each toxcard entry contains over 80 data fields , with 50 data fields devoted to chemical and toxicological / medical data and 30 data fields ( each ) devoted to describing the toxin target(s ) . 

figure 1.a screenshot montage of the toxin , toxin - target database ( t3db ) showing several of t3db s search and display tools describing the toxin toxaphene .
left : toxin browse view ; toxcard for toxaphene ; chemical structure similarity search for tozaphene ; t3db chemquery window ; t3db data extractor for toxin and toxin - target data fields .
a screenshot montage of the toxin , toxin - target database ( t3db ) showing several of t3db s search and display tools describing the toxin toxaphene .
clockwise from top left : toxin browse view ; toxcard for toxaphene ; chemical structure similarity search for tozaphene ; t3db chemquery window ; t3db data extractor for toxin and toxin - target data fields .
a toxcard begins with various identifiers and descriptors ( names , synonyms , compound description , structure image , related database links and i d numbers ) , followed by additional structure and physico - chemical property information .
the remainder of data on the toxin is devoted to providing detailed toxicity and toxicological data , including route of delivery , mechanism of action , medical information and toxicity measurements .
each of these targets are described by some 30 data fields that include both chemical and biological information , as well as details on their role in the mechanism of action of the toxin .
in addition to providing comprehensive numeric , sequence and textual data , each toxcard also contains hyperlinks to other databases , abstracts , digital images and interactive applets for viewing molecular structures . a key feature that distinguishes the t3db from other on - line toxin or toxicology resources is its extensive support for higher - level database searching and selecting functions .
in addition to the data viewing and sorting features already described , the t3db also offers a local blast ( 9 ) search that supports both single and multiple sequence queries , a boolean text search based on kinosearch ( http://www.rectangular.com/kinosearch/ ) , a chemical structure search utility based on chemaxon s marvinview , and a relational data extraction tool similar to that found in drugbank and the hmdb ( 1 ) .
these can all be accessed via the database navigation bar located at the top of every t3db page .
t3db s simple text search box ( located at the top of most t3db pages ) supports text matching , text match rankings , mis - spellings ( offering suggestions for incorrectly spelled words ) and highlights text where the word is found .
t3db s textquery function uses the same kinosearch engine , but also supports more sophisticated text querying functions ( boolean logic , multi - word matching and parenthetical groupings ) as well as data - field - specific queries such as finding the query word only in the  compound source field .
t3db s sequence searching utility ( seqsearch ) allows users to search through t3db s collection of 1300 known ( human ) toxin targets .
this service potentially allows users to identify both orthologous and paralogous targets for known toxins or toxin targets .
it also facilitates the identification of potential targets from other animal species . with seqsearch , gene or protein sequences
may be searched against the t3db s sequence database of identified toxin - target sequences by pasting the fasta formatted sequence ( or sequences ) into the seqsearch query box and pressing the  submit button .
t3db s structure similarity search tool ( chemquery ) can be used in a similar manner as its seqsearch tool .
users may sketch ( through chemaxon s freely available chemical sketching applet ) or paste a smiles string ( 10 ) of a query compound into the chemquery window . submitting the query launches a structure similarity search that looks for common substructures from the query compound that matches the t3db s database of known toxic compounds .
users can also select the type of search ( exact or tanimoto score ) to be performed .
high - scoring hits are presented in a tabular format with hyperlinks to the corresponding toxcards ( which in turn links to the targets ) .
the chemquery tool allows users to quickly determine whether their compound of interest is a known toxin or chemically related to a known toxin and which target(s ) it may act upon .
in addition to these structure similarity searches , the chemquery utility also supports compound searches on the basis of chemical formula and molecular weight ranges . the t3db s data extraction utility ( data extractor ) employs a simple relational database system that allows users to select one or more data fields and to search for ranges , occurrences or partial occurrences of words , strings , or numbers .
the data extractor uses clickable web forms so that users may intuitively construct sql - like queries .
using a few mouse clicks , it is relatively simple to construct complex queries (  find all toxins that target acetylcholinesterase and are pesticides ) or to build a series of highly customized tables . the output from these queries
t3db has a perl - based web - friendly front - end attached to a sophisticated mysql relational database ( version : 5.0.51a ) .
the database is maintained on an apple xserve located on the university of alberta campus .
all data is entered directly onto the database s ruby on rails web - based laboratory information management system ( t3-lims ) .
each toxcard and targetcard has an edit page , which allows administrators to manually make changes to the database entries . the public user interface and the lims both read from the same database , and there is no intermediate database for rendered html pages .
this hub is a restful web resource that automatically stores and updates chemical properties such as molecular weight , solubility and log p. additionally , the hub renders the structure images and thumbnails visible on the public site .
t3db s structure hub uses a combination of jchem base ( from chemaxon ) and ruby on rails running in a jruby environment on a glassfish server .
the centralized nature of this hub helps to maintain consistency for all structures stored in t3db .
whenever a structure is changed or fixed , all properties are automatically re - calculated and made available on the public site .
unlike the situation for drugs where formal approval processes and tight regulations allows one to easily identify whether a compound is a drug or not , the situation for toxins is not so simple .
first , there is the issue of defining exactly what a toxin is . normally , the word 
given that many man - made toxic substances are also produced by living organisms or are the byproducts of living organisms ( albeit at low concentrations ) , this distinction seems a little arbitrary .
therefore we have chosen to use the term toxin to refer to both man - made and naturally produced substances that exhibit some form of toxicity ( i.e. an acute reaction , injury or death ) . in constructing the t3db a distinction between  all posssible toxins and
technically almost all of the 38-million known chemical substances ( 11 ) could be toxic if consumed , injected or inhaled in sufficient quantities .
yet only a tiny fraction of known chemicals ever make it out of the laboratory and into everyday use ( perhaps < 20 000 compounds ) . therefore 
common toxins would have to be defined as those compounds that can be found in the home , the environment or the workplace and which of have had a recorded medical consequence ( i.e. acute reaction , injury or death ) . while this definition may seem reasonable
for instance , essential compounds such as vitamins , sugar , oxygen and even water can be prove to be toxic if consumed / inhaled in extreme excess .
yet their inclusion in a toxin database like t3db would be certainly stretch the limits of believability .
therefore we chose to further refine the inclusion criteria to limit ourselves to those compounds that have been routinely identified as hazardous in relatively low concentrations ( < 1 mm for some , < 1 m for others ) and which appear on multiple toxin / poison lists provided by government agencies such as toxnet ( 12 ) or the toxicological and medical literature . in each case , the toxicity of each compound was assessed by examining the available toxicity measurements and health effects , such as minimum lethal dose , ld50 , lc50 values and carcinogenicity . furthermore , because many common toxic substances , such as cleaning agents , gasoline , kerosene , glue , paint thinners are complex mixtures of many compounds , we also limited t3db to include only those substances where specific toxic components could be identified and where the chemical structures to those components were known . as a result , common or name - brand household cleaning products are not included in t3db but their toxic components are
. obviously these criteria may lead to the exclusion of some rare or interesting toxic compounds or toxic mixtures , but our focus for t3db was on creating a chemically - oriented database that could be broadly useful , comprehensively annotated and easily managed .
as has been previously noted , t3db toxins were identified using a number of methods , including literature surveys , data mining of other databases , using toxicology textbooks and examining lists of controlled or banned substances .
the toxic compounds found using these sources were also used to derive additional substances that were toxic by relation ( such as metal salts or structurally similar compounds ) and which can be found in the household , workplace or environment . once identified the toxins were further assessed using the 
common toxin inclusion criteria described above . in order to ensure both completeness and correctness , each toxin record entered into t3db was reviewed and validated by a member of the curation team after being annotated by another member .
additional spot checks were routinely performed on each entry by other members of the curation group .
several software packages including text - mining tools , chemical parameter calculators and protein annotation tools were developed , modified and used to aid in data entry and data validation .
this includes search tools such as biospider ( 13 ) and polysearch ( 14 ) , which collate and display text ( as well as images ) from multiple sources allowing t3db s curators to compare , assess , enter and correct toxin and toxin - target information .
much of the annotation in t3db was done manually , especially in areas regarding toxicology and biology , such as mechanisms of action , route of delivery , health effects and target identification .
this qualitative and quantitative information was derived from a variety of sources , including scientific journals , government records , material safety data sheets ( msds ) , textbooks , encyclopedias and existing toxicology databases .
for example , we frequently used existing chemical - protein or chemical gene interaction databases such as the ctd and stitch ( 15 ) to identify potential toxin targets .
once these potential targets were identified , the corresponding references were manually reviewed by multiple curators to confirm which of the genes / proteins were true targets . in annotating the toxic action of drugs
, we often used the drug mechanism information found in t3db s sister database drugbank . to facilitate and monitor the data entry process , all of t3db
s data is entered into a centralized laboratory information management system ( lims ) , allowing all changes and edits to the t3db to be monitored , time - stamped and automatically transferred .
relative to other recently published toxic substance databases , t3db probably has the smallest number of toxins or poisons in its collection ( 2900 in t3db versus 500 000 compounds in actor ) .
this situation was quite deliberate as t3db was designed to be a database for common toxins as opposed to a database for all known toxic substances .
while t3db s breadth of coverage is limited , it depth of coverage is not . with more than 80 data fields for each toxin and with more than 16 gb of data ,
we believe t3db offers a considerable amount of useful chemical , biological and toxicological data . as with most toxic substance databases t3db
this usually indicates that the data has yet to be measured or the information has yet to be reported in the literature . in some cases ,
the data probably exists , but our annotation team has yet to locate or validate it .
in addition to the existence of empty data fields , t3db is also missing some compounds . currently more than 500 compounds are still on the t3db  to do list and will be added ( at a rate of 50 compounds a week ) to the database over the coming months .
furthermore , new toxins are always being identified and these will need to be added as they are reported ( if sufficient information exists ) . because t3db strives for in - depth coverage , not all toxic compounds make it to the database . those that lack any significant biological or toxicological data ( i.e. the claim for toxicity is not supported by any study or biomedical report ) or those that do not have a known chemical structure will not be included in the database . despite these caveats and limitations , we believe t3db represents a new and important model for toxic substance databases . with a focus on depth as opposed to breadth , we are hopeful that the rich content in t3db will allow researchers , educators and members of the general public to uncover answers to many common questions about toxins and poisons . likewise , with its unique emphasis on
 common substances ( i.e. those that can normally be detected with modern analytical methods ) we believe that the t3db should also prove to be a valuable resource in toxico - metabolomics and clinical toxicology research .
the fact that t3db provides a wide range of chemical and biological data as well as a broad collection of search and display tools also represents a significant new development for toxic substance databases .
we are certainly hoping that some of these ideas may find there way into other toxic substance databases . over the coming two years we also plan to bring in additional data ( spectroscopic , tissue / biofluid concentration data ) and to add new features ( spectral matching , pathway images , target prediction ) to this database , with the intent of making t3db a comprehensive , one - stop - shop for toxicological and toxico - metabolomics research .
alberta advanced education and technology ( aaet ) ; the canadian institutes of health research ( cihr ) ; genome alberta , a division of genome canada . funding for open access charge : canadian institutes of health research .
 in an effort to capture meaningful biological , chemical and mechanistic information about clinically relevant , commonly encountered or important toxins , we have developed the toxin and toxin - target database ( t3db ) . 
 the t3db is a unique bioinformatics resource that compiles comprehensive information about common or ubiquitous toxins and their toxin - targets into a single electronic repository . 
 the database currently contains over 2900 small molecule and peptide toxins , 1300 toxin - targets and more than 33 000 toxin - target associations . 
 each t3db record ( toxcard ) contains over 80 data fields providing detailed information on chemical properties and descriptors , toxicity values , protein and gene sequences ( for both targets and toxins ) , molecular and cellular interaction data , toxicological data , mechanistic information and references . 
 this information has been manually extracted and manually verified from numerous sources , including other electronic databases , government documents , textbooks and scientific journals . 
 a key focus of the t3db is on providing  
 depth over  
 breadth with detailed descriptions , mechanisms of action , and information on toxins and toxin - targets . 
 t3db is fully searchable and supports extensive text , sequence , chemical structure and relational query searches , similar to those found in the human metabolome database ( hmdb ) and drugbank . 
 potential applications of the t3db include clinical metabolomics , toxin target prediction , toxicity prediction and toxicology education . 
 the t3db is available online at http://www.t3db.org . 
INTRODUCTION
DATABASE DESCRIPTION
DATABASE IMPLEMENTATION
CRITERIA FOR INCLUSION IN T3DB
QUALITY ASSURANCE, COMPLETENESS AND CURATION
LIMITATIONS AND CONCLUSION
FUNDING