Mammalian Toxicology, Session 1

What is toxicology?

Definition: Study of deleterious effects of chemicals

Comparison to Pharmacology (Study of medical properties of chemicals) or Endocrinology (Study of physiological responses to endogenous chemicals)

What are toxins?

Naturally occurring compounds that may demonstrate deleterious effects when introduced into another organism.

What are toxicants?

Compounds of anthropomorphic origin that demonstrate deleterious effects when introduced into an organism.

Some considerations of historical background:

The classical Greeks started classifying those poisons that they encountered in conduct of their daily lives as being derived from mineral, plant (& fungal), or animal sources.

Important examples of toxicants that the ancients might have encountered include heavy metals (Hg, Cu, Pb, Sn) or homologs of S such as Ar. These are all found abundantly in minerals and soils from volcanic areas and are elements released in the heating of ores during refinement of metals. During the Bronze age this would have been common. Arsenic is also found in soils such as those in India and Bangladesh where it can be leached into drinking water.

Examples of toxins would occur in plants, fungi, and animals. The poison ivy family (poison ivy, poison sumac, poison oak, cashew, shellac, mango...) all produce a mixture of reactive oils called urushiol. This can cross-link and otherwise modify self-proteins resulting in generation of an immune response. Presence of immune memory often results in an anaphylactic type response upon repeated exposure (so long as the offending urushiol is allowed time to be absorbed and to react with proteins in a manner similar to the initial sensitizing exposure). Hemlock, nightshade (including the precursors of tomato, potato, and sunflower), jimpsom weed, and others contain chemicals toxic to potential plant predators. Many large fruited plants including apples, peaches, and apricots have seeds encased in very hard coverings within otherwise very edible, fleshy fruit. The seeds often contain cyanoglycosides which generate HCN when digested in stomach acid. Again, the toxins appear to be deterrents to predation, this time of the seeds. Fungi related to the Amanita mushrooms as well as other varieties also produce toxins. For plants these toxins appear to serve as defense mechanisms. (A toxicology of plants is found in: http://www.fao.org/docrep/x2230e/x2230e15.htm )

Animals such as poisonous snakes, arachnids, many mollusks (including jellyfish, cone shells, and some ocotopi), and certain insects like wasps or hornets use toxins both for protection, and, more importantly as a means for food procurement. The array of tissues affected in mammals by the venoms of snakes, arachnids, and mollusks is very large. It includes the CNS, peripheral nerves, respiratory centers, voluntary muscles, vascular endothelium, specific blood cell types, heart, kidney, immune system, among others. Likewise the manner in which the toxins from arachnids or fish or mollusks act on insects or other fish is similarly broad.

These classifications make sense for the ancient world. Many of them would be known to shamans and other traditional healers or keepers of cultural history, tradition, and lore.

But what about bacterial toxins, as the ancient world would not have known of these?

The endotoxins produced within an organism following infection by a bacterium non localized to the digestive tract or external integument are responsible for many of the symptoms associated with these disease conditions. Again, they may affect a wide variety of systems and may do so by a wide spectrum of means which may include impacting immune function, continually activating signal transducers involved in endocrine or nervous signal transduction, or inhibiting the elongation factors involved in cellular protein synthesis. Bacteria such as the "O" strain of E. coli, Clostridium botulinum, Staphylococcus aureus, Bacillus anthracis, Vibrio cholerae, or Corynebacterium diphtheriae all act as pathogens by generating potent endotoxins within infected hosts.

What about viruses?

Viruses or certain bacteria may induce their hosts to produce toxins. Vibrio do not generate toxin unless they are infected by certain bacterial viruses. The Red Tide is generated by algae that have become infected by certain bacteria.

What about prions, the infective agents for slow viruses? Are these toxins in an of themselves as they directly induce a deleterious consequence in an infected host?

During the late middle ages and into the early Renaissance the idea of evaluating the impacts of potential poisons arose. Looking at what organs were effected by a poison became an important idea as did evaluating the impact of a poison on a test subject, e.g., a test on a dog might be done before applying a poison to a human. Paracelsus also stated the central tenant that effect was proportional dosage. Not only did this play a central role in formulating toxicology, but it formed a pillar of pharmacology and endocrinology as well. Moreover, the idea that a deleterious substance might be less deleterious if given in a small dose and, in fact, possibly even beneficial, ultimately gave rise to the train of thought leading to part of homeopathic medicine.

What is homeopathic medicine? Holistic medicine? Allopathic medicine?

How do these forms of medicine approach the topics of toxicants, toxins, and toxicology?

Paracelsus' idea that responses to chemicals, toxins, or toxicants was graded ultimately leads to the idea of a Dose-Response curve. This is an underlying tenant of endocrinology, pharmacology, and toxicology. The normal curvilinear response reflects the underlying enzymatic machinery responsible for "running" each cell. It is the cumulative sum of the activities of the enzymes within any given cell and the summation of the activities or responses of each single cell within a tissue, organ, or organism. For single celled organisms, or for measures of whole organism response such as lethality, it is the population response. Again, a cumulative sum of the activities of each individual cell or organism and its component parts.

For a given response, say a lethal response, the curve rises from a basal nadir asymptote along a smooth curve to a maximal asymptote. The maximum results from saturation either of cellular systems or of a population, e.g., 100% deaths. The inflection point of the curve falls at 50% of maximal response. The dose corresponding to this level of response is termed the LD50 in lethality assays or the ED50 in assays of nonlethal response.

Would it be possible to have a lethality assay in which the maximal level of response was less than 100%? Why?

In assessments for nonlethal response, the dose response may be biphasic, rising from a basal low value (rising response) to a maximum peak or plateau, and then declining at higher doses back toward or beyond baseline. Thus, the low dose end of the biological response to the chemical may be positive, e.g., palliative, as in pharmacologic or endocrine compounds, while the high dose end is negative or toxic. The distance between these regions of response constitutes the margin of safety for a particular drug or a chemical used for purposes other than as a poison.

Toxicology includes consideration of the factors that determine margin of safety, or relative risks associated with exposure to a particular toxicant or toxin.

When we say "dose," what kind of dose is referred to? What are the routes of exposure to toxicants and toxins? What physiological barriers stand between a toxicant and its ultimate cellular target(s)? Does the form of the toxicant play any role in exposures or penetration of physiological barriers?

Is it possible to have a threshold value for a toxicant below which there is no effect? What are the reasons or mechanisms that might underlie such a threshold if it does exist?

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