Healthcare

The Toxicology Laboratory

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Toxicology laboratories serve a variety of purposes, ranging from forensic (law-related) testing and analysis for a broad range of biological samples to support coroners, government and law enforcement agencies, medical examiners, physicians, researchers and others in corporate and legal industries, to pain management, clinical diagnostics, environmental and ecological testing and more. At it's essence, "analytical toxicology is the detection, identification, and measurement of foreign compounds (xenobiotics) in biological and other specimens. Analytical methods are available for a very wide range of compounds: these may be chemicals, pesticides, pharmaceuticals, drugs of abuse [man-made poisons are termed "toxicants"] and natural toxins."[1]

Usually toxins or toxicants are classified "based on their chemical nature, mode of action, or class (exposure class and use class). The exposure class classifies them as occurring in food, air, water, or soil. The use class classifies drugs as drugs of abuse, therapeutic drugs, agriculture chemicals, food additives, pesticides, plant toxins (phytotoxins), and cosmetics."[2]

Some example of drugs tested for by tox labs include antidepressants; antipsychotics; opiates and pain medications; cannabis (both synthetic and “natural”), cocaine, amphetamine/methamphetamines; cathioniones; benzodiazepines; zolpidem; ketamine; phencyclidine; methadone and metabolites for any of a variety of substances, plus heavy metals, pesticides and any other substance that can be a toxin (poison). There are in fact very few substances at all that, if used at sufficiently dosage, aren't toxic - including things like vitamins, nutrients and other substances not ordinarily regarded as poisons.[3]

History

No doubt from the earliest moments of humanity, we have been trying experiments as to what is edible/ingestible and what is poisonous, as a species. Probably the earliest recorded methodical effort to do so was by Shen Nung, called the Father of Chinese Medicine, around 2695 BC. He used himself as the subject when trying 365 herbs, and, somewhat predictably, ended up dying of a toxic overdose. However, he did manage to write On Herbal Medical Experiment Poisons before succumbing, which was used as an indispensable reference for the next thousand years or so and is responsible for the great depth and breadth of herbal expertise so characteristic of traditional Eastern medicine.[4]

Lithograph of Mathieu Orfila

From Wikipedia:

[In western civilization] Dioscorides, a Greek physician in the court of the Roman emperor Nero, made the first attempt to classify plants according to their toxic and therapeutic effect.[5] Ibn Wahshiyya wrote the Book on Poisons in the 9th or 10th century.[6] This was followed up in 1360 by Khagendra Mani Darpana.

...In 1850, Jean Stas became the first person to successfully isolate plant poisons from human tissue. This allowed him to identify the use of nicotine as a poison in the famous Bocarmé murder case, providing the evidence needed to convict the Belgian Count Hippolyte Visart de Bocarmé of killing his brother-in-law.[7]

Theophrastus Phillipus Auroleus Bombastus von Hohenheim (1493–1541) (also referred to as "Paracelsus", from his belief that his studies were above or beyond the work of Aulus Cornelius Celsus – a Roman physician from the first century) is also considered "the father" of toxicology.[8] He is credited with the classic toxicology maxim, "Alle Dinge sind Gift und nichts ist ohne Gift; allein die Dosis macht, dass ein Ding kein Gift ist." which translates as, "All things are poisonous and nothing is without poison; only the dose makes a thing not poisonous." This is often condensed to: "The dose makes the poison" or in Latin "Sola dosis facit venenum".[9][10]

Modern toxicology has proceeded from Paracelsus, and includes some milestones in the 18th and 19th centuries. These include Bernardino Ramazzini, called the Father of Occupational Medicine, who wrote Diseases of Workers in 1700. In 1761, John Hill noted an apparent relation of snuff to nasal cancer. Percival Pott identified the link between chimney soot and scrotal cancer in 1775.[11][12]

The Father of Modern Toxicology, Mathieu Orfila, from Minorca, Spain, worked at the University of Paris and, in 1815, published the first book devoted exclusively to toxicology, Traité des poisons, also called Toxicologie générale.[13]. An English translation in 1817 was entitled A General System of Toxicology or, A Treatise on Poisons, Found in the Mineral, Vegetable and Animal Kingdoms, Considered in Their Relations with Physiology, Pathology and Medical Jurisprudence.

Its importance in forensic science has continued and grown, while also spawning additional areas of importance, including environmental and ecological toxicology, and testing for addiction treatment, probation and employment purposes. Focus has turned in recent decades from merely describing linkages, to the mechanisms of toxicity, with molecular biology and other research techniques contributing to rapid advances in various areas of toxicology..[11]

Types of Tox Labs

There are a number of ways to break down the general discipline of toxicology into more specific areas. For instance, there is descriptive toxicology, which generally characterizes its earlier history, concentrating on identifying and describing toxins/toxicants, and mechanistic toxicology, which focuses on the mechanisms of poisons: how they work. Combining the approaches and purposes of toxicology labs provides a generally accepted breakout of the types of toxicology practiced today:

  • Clinical toxicology. Diagnosis and treatment of overdoses of drugs, poisonings, etc. It also deals with identifying the compound and the amount of toxin present in the body. It differs from forensic toxicology primarily in that subjects are living. Thus, it often involves a study of toxicokinetics, the study of how the levels of toxicants and their metabolites change over time, the time that it takes to eliminate toxicants after exposure, and ways in which the toxic effects of various poisons can be reduced in persons who have been exposed, or how elimination of the toxicant can be increased. Teratology is a subset concentrating on embryonic toxicology.[14][15]
  • Forensic toxicology. Essentially, this is toxicology as applied to legal/court operations. It involves the study of cause of death, extracting toxicants from specimens and determining the type and amount present, as well as establishing the relation between residual levels of toxins and the cause of death. Forensic toxicologists work with pathologists, medical examiners and coroners.[16]
  • Chemical toxicology. This discipline focuses specifically on chemical toxins: their structure, mechanism and toxic effects on organisms.
    Aquatic toxicologist at the Upper Midwest Environmental Sciences Center - U.S. Geological Survey
  • Aquatic toxicology. An offshoot of the general ecological/environmental toxicology focus that emerged largely based on Rachel Carson's book Silent Spring, published in 1962. It is the study of effects of toxins on water-dwelling organisms. Toxicants include manufactured chemicals, like pesticides and by-products, as well as natural substances. Includes study of subcellular-level mechanisms in aquatic organisms, e.g. certain shrimp in estuaries, etc.
  • Ecotoxicology. Study of the effect of toxins at all levels of biological organization, or ecosystems, from molecular level to the level of the macro ecosystem.
  • Industrial toxicology. This discipline is involved specifically with the study of effects of industrial chemicals on organisms and the environment. It includes the safety of workers of the industry, their exposure to chemicals and identification and introduction of effective safety measures.
  • Environmental toxicology. This branch deals with the study of the toxic effects of various substances on the environment. Deals with the study of effects of pollution of water, soil, air and the effects of pollutants on organisms and distribution and movement of chemicals in the environment and how long residual traces persist.
  • Biochemical and molecular toxicology. This is toxicology at molecular levels, including at the DNA level. It includes study of toxicant-related genetic mutations and methods of mitigation, prevention and treatment/reparation. It may also include specializations in research and/or teratology (embryonic toxicology).
  • Product development toxicology. As part of overall QA/QC, product development toxicology tests manufactured products for toxicity before they are released to the market. It informs and drives modifications and improvements to ensure absence, or safe levels, of possible toxins. In pharmaceutical development and production, testing helps establish safe dosages, storage and usage.
  • Regulatory toxicology. The regulatory toxicologist's mission is to identify environmental and product risks and advise the public and lawmakers. This includes things like establishing thresholds of solvent vapors in industries and safe levels of drugs and other substances for any organisms (humans, animals or plants).
  • Toxicogenomics. Genetic toxicology, or toxicogenomics is the study of the effects of chemicals and other environmental agents that can cause mutations (mutagens) or cancer (carcinogens). It includes study of clastogens, responsible for breaks and rearrangements of chromosomes.[15][14]

Testing and Processes

Standard Drug Report
There are as many toxicology tests as there are toxins/toxicants to detect. And since virtually any substance can be toxic in sufficient amounts, it would be impossible in practical terms to test for all toxins in every case. Therefore, toxicology labs conduct tests (a) appropriate to their particular toxicology specialization and (b) based on practical expectations (at least for initial screens). The types of specimens also vary. For instance, a drug screening lab may deal exclusively with perhaps a dozen or so common substance detection screens and receive urine and/or whole blood, plasma or serum as specimens. A medical examiner's tox lab may add a wider range of substances, and also test other bodily fluids, tissue, hair or even clothing or other articles. Of course an environmental, eco or aquatic tox lab is interested in detecting levels of EPA-controlled toxicants.

What each lab does with the results of its testing also varies depending on its mission. They may become part of a police case report, public record, EPA report generating a fine or other penalty, contribute to a research project, inform a patient treatment program, etc.

With regard to a data management system (LIMS), the expectation must be that it be able to handle the variations mentioned, in sample type, analyses and reporting, plus a selection of ancillary functions (e.g. inventory, invoicing, instrument management, etc.), in order to be truly labeled a data management solution for toxicology. The alternative is to use a highly specialized LIMS designed specifically for a given type of tox lab. The possible drawback in that case, however, is that it is hard-coded and inflexible, which can be problematic if it becomes desirable to create modifications or additions to procedures or methods/analyses, or to reporting activities. Most modern professional systems, however, are designed with the flexibility required to meet the diverse requirements of the different toxicology lab variations, both initially and dynamically over time as they evolve. The most successful ones allow users to largely configure to their own specs, rather than requiring development in most cases.[17][18]

Standards and Regulations

Standards and regulations help ensure any type of laboratory provides meaningful results, and it is certainly no different for any of the various types of tox labs. Meeting and/or exceeding these is a prime consideration, and in fact is one of the compelling drivers for the decision to use a dedicated software to manage data processing. A Laboratory Information Management System (LIMS) and Laboratory Information System (LIS) are two terms used to describe such a system, with the difference being that the latter term tends to be more commonplace in medical settings. Today's LIMS and LIS share features and functionality to such a degree that the distinction has all but disappeared, and the terms are merely a function of usage.[19]

The Toxic Substances Control Act of 1976 gives the Environmental Protection Agency (EPA) (established in 1970) the power to ban or restrict the manufacture or use of any chemical that it deems hazardous. The Act also authorizes the EPA to require testing of potentially harmful chemical substances already on the market. The Federal Insecticide, Fungicide, and Rodenticide Act requires that all pesticides distributed in the United States be registered.

The Occupational Safety and Health Administration (OSHA), created in 1971, is responsible for regulating safety in the workplace. OSHA uses both epidemiological and animal studies to make regulatory decisions regarding toxins. Finally, the Consumer Products Safety Commission (CPSC) is responsible for maintaining a clearinghouse of information about the hazards associated with the use of consumer products.[20]

Forensic tox labs are provided guidelines by the Society of Forensic Toxicologists (SOFT), Society of Toxicological and Forensic Chemistry (GTFCh), TIAFT (The International Association of Forensic Toxicologists), American Board of Forensic Toxicology, Inc. (ABFT) and the toxicology section of the American Academy of Forensic Sciences (AAFS), among others, and may be regulated by SAMHSA (the US Substance Abuse and Mental Health Services Administration, administered through HHS) and/or CAP (College of American Pathologists). Forensic LIMS will want to support data transfer that meets the National Institute of Justice’s (NIJ) Forensic Information Data Exchange (FIDEX) standards.[21] In a clinical setting, HIPAA, CLIA and HITECH regulations apply in most cases, along with National Academy of Clinical Biochemistry (NACB) standards or ACB (Association of Clinical Biochemists), GCLP (Good Clinical Laboratory Practices) and any applicable state and local laws. Outside of that, your tox lab may be subject to 21 CFR part 11, ISOs and others. All are guided by GLP/GALP. In some applications, standards and regs may address timeliness of results in addition to analytical methods and procedures. Since there are a number of varieties of forensic labs, areas of regulation and standards may be broken down into particular areas:

  • Forensic toxicology
  • Workplace drug testing
  • Driving under the influence of alcohol/drugs
  • Clinical toxicology (poisoning in emergency medicine,substitution programs)
  • Point-of-care testing
  • An overlap area (brain death, drugs of abuse, sexual assault cases)[22]

Aquatic and environmental toxicology labs test to National Pollutant Discharge Elimination System (NPDES) US EPA standards, as specified in permits issued by the EPA, who also regulate permits for stormwater, water treatment, wastewater, pesticides, animal feed and other areas. The aquatic tox lab may use WET tests (whole effluent toxicity) and other direct aquatic toxicity tests.[23]

Even though standards and regulations for each type of tox lab may vary, most major Laboratory Information Management Systems (LIMS) will support any/all of them fully, with the added benefit of providing easy and swift retrieval of necessary records during audits.[21]

References

  1. "International Programme on Chemical Safety: Analytical Toxicology". World Health Organization (WHO). 2016. http://www.who.int/ipcs/publications/training_poisons/analytical_toxicology/en. Retrieved 12/14/2016. 
  2. "Toxicological screening". NCBI/NIH, Journal of Pharmacology & Pharmacotherapeutics. Apr-Jun 2011. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3127354. Retrieved 12/14/2016. 
  3. "Toxicology Tests". XperTox. 2016. http://www.expertox.com/html/services/toxicology.php. Retrieved 12/15/2016. 
  4. "Shen Nung". Toxipedia. July 18, 2012. http://www.toxipedia.org/display/toxipedia/Shen+Nung. Retrieved 12/15/2016. 
  5. Hodgson, Ernest (2010). A Textbook of Modern Toxicology. John Wiley and Sons. p. 10. ISBN 0-470-46206-X. 
  6. Levey, Martin (1966). Medieval Arabic Toxicology: The Book on Poisons of ibn Wahshiyya and its Relation to Early Native American and Greek Texts. 
  7. Wennig, Robert (April 2009). "Back to the roots of modern analytical toxicology: Jean Servais Stas and the Bocarmé murder case". Drug Testing and Analysis (journal) (England) 1 (4): 153–155. doi:10.1002/dta.32. PMID 20355192. 
  8. "Paracelsus Dose Response in the Handbook of Pesticide Toxicology WILLIAM C KRIEGER / Academic Press Oct01". http://www.mindfully.org/Pesticide/Paracelsus-Dose-ToxicologyOct01.htm. 
  9. Ottoboni, M. Alice (1991). The dose makes the poison : a plain-language guide to toxicology (2nd ed.). New York, N.Y: Van Nostrand Reinhold. ISBN 0-442-00660-8. 
  10. "Toxicology/History". Wikipedia. December 10, 2016. https://en.wikipedia.org/wiki/Toxicology#History. Retrieved December 15, 2016. 
  11. 11.0 11.1 "A Brief History of Toxicology". Aibolita. http://aibolita.com/sundries/22157-a-brief-history-of-toxicology.html. Retrieved December 15, 2016. 
  12. "Snuff-induced malignancy of the nasal vestibule: a case report". NCBI/NIH. Sept-Oct 2007. https://www.ncbi.nlm.nih.gov/pubmed/17826541. Retrieved December 15, 2016. 
  13. "Biography of Mathieu Joseph Bonaventure Orfila (1787–1853)". U.S. National Library of Medicine. https://www.nlm.nih.gov/visibleproofs/galleries/biographies/orfila.html. 
  14. 14.0 14.1 "Toxicology Specialty Areas". Encyclopedia.com. http://www.encyclopedia.com/science/encyclopedias-almanacs-transcripts-and-maps/toxicology-specialty-areas. Retrieved December 17, 2016. 
  15. 15.0 15.1 "Branches of Toxicology - What are Toxins?". Biotechnology Forums. http://www.biotechnologyforums.com/thread-1671.html. Retrieved December 17, 2016. 
  16. "What Is Forensic Toxicology?". The Forensic Toxicology Council. July, 2010. http://webcache.googleusercontent.com/search?q=cache:http://www.swgtox.org/documents/WHAT_IS_FORENSIC_TOXICOLOGY.pdf. Retrieved December 17, 2016. 
  17. Ben Tagger. "An Introduction and Guide to Successfully Implementing a LIMS (Laboratory Information Management System)". Computer Science Department, University of Wales, Aberystwyth. http://www0.cs.ucl.ac.uk/staff/B.Tagger/LimsPaper.pdf. Retrieved December 20, 2016. 
  18. "LIMS feature". LIMSwiki.org. September 9, 2013. http://www.limswiki.org/index.php/LIMS_feature. Retrieved December 20, 2016. 
  19. "Laboratory information management system". Wikipedia. 28 October 2016. https://en.wikipedia.org/wiki/Laboratory_information_management_system. Retrieved December 17, 2016. 
  20. "Animals and Alternatives in Testing: History, Science, and Ethics, Ch. 3 Toxicology and Toxicity Testing". Johns Hopkins Bloomberg School of Public Health. http://caat.jhsph.edu/publications/animal_alternatives/chapter3.html. Retrieved December 19, 2016. 
  21. 21.0 21.1 "What Constitutes a Good Forensics LIMS?". Scientific Computing. 10/04/2011. https://www.scientificcomputing.com/article/2011/10/what-constitutes-good-forensics-lims. Retrieved December 19, 2016. 
  22. Joris Penders, Alain Verstraete (3 May 2006). "Laboratory guidelines and standards in clinical and forensic toxicology". ResearchGate. https://www.researchgate.net/publication/225749577_Laboratory_guidelines_and_standards_in_clinical_and_forensic_toxicology. Retrieved December 19, 2016. 
  23. "Toxicity Testing Laboratory". Marinco Bioassay Laboratory. 2009. http://www.toxicitylab.com/content/laboratory/toxicity_testing.php. Retrieved December 19, 2016.