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TOXIC! TOXIC! TOXIC!


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Toxicology: Not another MT thingy!





History & Milestones

Year
Development
Early 1500s
Paracelsus provides a scientific basis for understanding poisons.
1809
F. Magendie reports on the mechanisms of action of arrow poisons.
1830–40
Orfila devises methods for detecting poisons, thereby proving that poisoning had taken place and establishing the field of forensic toxicology.
1920s–30s
Delayed neurotoxicity in individuals who consume ‘bootleg liquor,’ in particular, ‘ginger jake’, contaminated with tri-o-cresyl phosphate.
1945
R. A. Peters, L. A. Stocken, and R. H. S. Thompson develop British anti-Lewisite (BAL) as an antidote for arsenic.
P. Muller introduces and studies DDT and related organochlorine compounds.
1952
G. Schrader introduces and studies organophosphorus compounds.
1950s
Over 200 cases of severe neurological disease reported in individuals consuming fish contaminated with methyl mercury in Minimata, Japan.
1984
Approximately 2000 die in Bhopal, India, from acute lung disease associated with methylisocyanate release.

Historically, toxicology laid the foundation of therapeutics and experimental medicine. Toxicology continues to develop and expand from the past century by assimilating techniques and knowledge from branches of biology, chemistry, physics and mathematics. Recently, a new field was added to toxicology which is the relevance of this discipline to security evaluation and risk assessment.

Scope and Definition  

Toxicology is defined as the branch of medical science that deals with poisons, which are substances that causes a detrimental effect when administered, either by accident or by plan, to a living organism especially to humans. By principle, toxicology also includes the study of harmful effects brought about by substantial phenomena, such as radiation, noise, and so on. Toxicology has also been defined as the study of the unfavorable effects of xenobiotics that has evolved from ancient poisoners. In practice, however, many complications exist beyond these plain definitions, both in bringing more accurate definition to the meaning of poison and to the quantification of toxic effects.




Fate and effect of toxicants in the body.



Areas of Toxicology



Graphical representation of the interconnections between different areas of toxicology.

Mechanistic toxicology is concerned with the identification and understanding of cellular, molecular, and biochemical mechanisms by which chemicals bring about toxic effects on living organisms.


Descriptive toxicology deals directly with toxicity testing, which provides information for safety evaluation and regulatory requirements. The appropriate toxicity tests in cell culture systems or experimental animals are intended to yield information to evaluate risks posed to humans as well as the environment from contact to specific chemicals.


Regulatory toxicology has the sole responsibility for deciding, on the starting point of data provided by descriptive and mechanistic toxicologists, whether a chemical or a drug poses a sufficiently low risk to be marketed for a declared purpose or consequent human or environmental exposure resulting from its use.


Sources of toxicants





Exposure Classes. Exposure classes include toxicants in food, air, water, and soil as well as toxicants characteristic of domestic and occupational settings.


Use Classes. Use classes include drugs of abuse, therapeutic drugs, agricultural chemicals, food additives and contaminants, metals, solvents, combustion products, cosmetics, and toxins. Some of these, such as combustion products, are the products of use processes rather than being use classes.

Routes
  • Ü  Gastrointestinal tract (ingestion)
  • Ü  Lungs (inhalation),
  • Ü  Skin (topical, percutaneous, or dermal)
  • Ü  Parenteral (other than intestinal canal) routes.


Toxic agents
  • Ü  Pesticides/herbicides/fungicides
  • Ü  Metals
  • Ü  Industrial chemicals
  • Ü  Vapors and gases
  • Ü  Naturally occurring toxins
  • Ü  Drugs


Toxicity Screening
  • 1.     Acute toxicity
  •    Ø  administration of progressively larger single doses up to the lethal dose
  •    Ø  “No-Effect” dose – largest dose at which a specific toxic effect is NOT seen
  •    Ø  Minimum Lethal Dose – smallest amount of the drug that can kill a study animal
  •    Ø  LD50 – dose that kills half of the experimental animal population

  • 2.     Subacute / chronic toxicity
  •    Ø  administration of multiple doses to detect any adverse effects

Mutagenicity
Ø  detection of possible ability to induce genetic alteration (mutation)
Carcinogenicity
Ø  detection of possible ability to induce abnormal clonal uncontrolled proliferation of genetically altered cells
Teratogenicity
Ø  detection of possible deleterious effects on the developing fetus


Most Common Causes of Poisoning

Circa 1964
Death
Disability
•        Barbiturates
•        Carbon monoxide
•        Phenols; Cresols
•        Methanol
•        Ethanol
•        Cyanide
•        Arsenic fluoride
•        Mercury
•        Salicylates
•        Ethanol
•        Barbiturates
•        Lead
•        Arsenic
•        Salicylates
•        Carbon monoxide
•        Methanol
•        Antihistamines
•        Nonbarbiturate hypnotics
•        phenothiazines



Food poisoning in the Philippines

  • Salmonella  - raw/contaminated meat, poultry, meat, egg yolks
  • Campylobacter – meat & poultry
  • Shigella – raw, ready to eat produce
  • Cryptosporidium – water, fruit, salad vegetables
  • E. coli – contaminated water, beef  (fecal)
  • Yersinia – inadequately cooked / raw pork
  • Listeria – inadequately cooked/raw pork
  • Vibrio – oysters & other shellfish
  • Cyclospora – imported fresh produce


Come bitter pilot, now at once run on
The dashing rocks thy seasick weary bark!
Here’s to my love! O true apothecary!
Thy drugs are quick. Thus with a kiss I die.
(Romeo and Juliet, act 5, scene 3)




Thank you and watch out for my next post! J




References:
Klaassen, Curtis. Casarett & Doull’s Toxicology the Basic Science of Poisons, 7th edition
McQueen, Comprehensive Toxicology 2nd edition
Hodgson, Ernest. A Textbook of Modern Toxicology 4th edition







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Endocrinology at a Glance



Location of different Endocrine glands.
Source: Tortora Gerald, Principles of Anatomy and Physiology 12th edition



Nearly a hundred years ago, Starling coined the term hormone to describe secretin, which is a substance that stimulates secretion of pancreatic juice and bile that is secreted by the small intestine via the blood stream. In his Croonian Lectures, Starling considered the endocrine and nervous systems as the main organ systems that works in coordination with each other in order to regulate and control bodily organ functions. Thus, endocrinology found its earliest domicile in the mammalian physiology discipline.

Over the next several decades, many works by physiologists, biochemists, and clinical investigators led to the categorization of an array of hormones secreted into the blood stream from discrete glands and/or other organs. These investigators were the first to show that diseases such as hypothyroidism and diabetes could be successfully treated by replacing specific hormones. These initial triumphs fashioned the foundation of the clinical specialty of endocrinology. Distinct advances in molecular biology, cell biology, and genetics over the consequent years began to help elucidate the mechanisms of hormone secretion and action and nature of endocrine diseases.

Both circulating and local hormones of the endocrine system contribute to homeostasis by the regulation of the growth and activity of the different target cells in the body. Hormones also participate in the regulation of body metabolism.

As boys and girls come into puberty, they start to develop remarkable differences in their behavior and physical appearances. There may be no other period in life so significantly shows the endocrine system’s impact in regulating body functions and directing development. In girls, estrogen promotes the buildup of adipose tissue in the breasts and hips, molding a feminine shape. Meanwhile, boys begin to build muscle mass and enlarge the vocal cords, producing a lower pitched voice; due to increasing production of testosterone in their body. These bodily changes are just a few examples of the powerful and dynamic influence of endocrine secretions. Perhaps, multitudes of hormones help maintain and regulate homeostasis in the body on a daily basis. They control the activity of cardiac muscle, smooth muscle, and some glands; modify body metabolism; prompt growth and development; manipulate reproductive processes; and take part in the circadian (daily) rhythms recognized by the suprachiasmatic nucleus of the hypothalamus.

Moreover, both the nervous and endocrine systems work hand in hand to bring together functions of all body systems. Bear in mind that the nervous system’s actions are made through nerve impulses (action potentials) that are conducted along axons of neurons. At synapses, nerve impulses elicit the release of substances called neurotransmitters which serves as mediator or messenger molecules. Also, the endocrine system controls the body’s activities by releasing mediators, called hormones. However, the means of control of the two systems are very different.

Responses of the endocrine system often are slower compare with those of the responses of the nervous system; even though some hormones act only within seconds, to be able to cause a response, most get several minutes or more. The effects of the activation of the nervous system are generally briefer than those of the endocrine system. The nervous system actually acts on specific muscles and glands. The endocrine system’s influence is much broader; it helps control almost all types of cells in the body.

Endocrine glands exude their products (hormones) not into ducts of the body, but into the interstitial fluid adjacent to the secretory cells. Then from the interstitial fluid, hormones disseminate into the blood capillaries and blood serves as carrier that will deliver them to target cells throughout the body. Since most hormones are required only in very small amounts, most of the time the circulating levels are typically low.

The endocrine glands include the pituitary, parathyroid, adrenal, pineal glands thyroid. In addition, several organs and tissues are not solely classified as endocrine glands but contain cells that liberate hormones. These include the hypothalamus, thymus, stomach, liver, small intestine, pancreas, ovaries, testes, kidneys, skin, heart, adipose tissue, and placenta. When taken together, all endocrine glands and cells that secrete hormones constitute the endocrine system. The vast body of knowledge that deals with the structure and function of the endocrine glands and the diagnosis and treatment of disorders of the endocrine system is endocrinology.






References:
Larsen, Reed et. al, William’s Textbook of Endocrinology 10th edition, 2003
Tortora Gerald, Principles of Anatomy and Physiology 12th edition, 2009

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