1. References
Casarett & Doull’s: Essentials of Toxicology, 2nd Ed., 2010 by Curtis Klaassen and John Watkins III
Poisoning and Drug Overdose, 6th Ed., 2012 by Kent R. Olson
Goldfrank's Toxicologic Emergencies, 10th Ed by Lewis R. Goldfrank
Emergency Toxicology, 2nd Ed., 1998 by Peter Viccellio

2. Department of Biopharmaceutics & Clinical Pharmacy
Toxicology ( )
(2 credit hours)
Dr. Khawla Abu Hamour
Department of Biopharmaceutics & Clinical Pharmacy
University of Jordan

3. TOXICOLOGY IN PERSPECTIVE
Introduction:
TOXICOLOGY IN PERSPECTIVE

4. DEFINITIONS & TERMINOLOGY
Toxicology: (toxicum) & (logia)….the Study of Poisons
(The science of poisons, including their source, chemical composition, action, tests, and antidotes).
Poisons: are drugs that have almost exclusively harmful effects
However, Paracelsus (1493–1541) famously stated that “THE DOSE MAKES THE POISON”
a substance that, on ingestion, inhalation, absorption, application, injection, or development within the body, in relatively small amounts, may cause structural or functional disturbance. Called also toxin
biologic origin, ie, synthesized by plants or animals, in contrast to inorganic poisons (lead and iron)
Toxicology: is the branch of pharmacology that deals with the undesirable effects of chemicals on living systems
Toxin a poison, especially a protein or conjugated protein produced by certain animals, higher plants, and pathogenic bacteria

5. Disciplines of Toxicology

6. TOXICOLOGY DISCIPLINES Applied Toxicology.
Environmental toxicology:
study the effects of chemicals that are contaminants of food, water, soil, or the atmosphere
Industrial (occupational) toxicology:
Toxic exposure in the work place or during product testing
Clinical (medical) toxicology: focus on the diagnosis, management and prevention of poisoning or ADEs due to medications, occupational and environmental toxins, and biological agents
Applied Toxicology. This includes the various aspects of toxicology as they apply in the field or the development of new methodology or new selective toxicants for early application in the field setting

7. TOXICOLOGY DISCIPLINES
Veterinary toxicology**
Forensic toxicology: is the use of toxicology to aid medical and legal investigation of death
Nanotoxicology: is the study of the toxicity of nanoparticles (<100 nm diameter). Because of large surface area to volume ratio, (nanomaterials have unique properties compared with their larger counterparts)
**is the diagnosis and treatment of poisoning in animals

8. What is a Poison?? “What is there that is not poison?
All things are poison and nothing without poison. Solely, the dose determines that a thing is nota poison”
Paracelsus ( )

9. Water Intoxication?
Water poisoning….fatal disturbance in brain functions when the normal balance of electrolytes in the body is pushed outside of safe limits (e.g., hyponatremia) by overhydration
Water, just like any other substance, can be considered a poison when over-consumed in a specific period of time
Intravenous LD50 of distilled water in mouse is 44ml/kg
Intravenous LD50 of isotonic saline in mouse is 68ml/kg
LD stands for "Lethal Dose". LD50 is the amount of a material, given all at once, which causes the death of 50% (one half) of a group of test animals

10. What is a Poison?? Poisoning or exposure??
Many people consider that poisoning start the moment exposure occurs
In reality, we are exposed to a wide variety of toxic substances each day from food and water that we ingest, and air that we breath
We do not display toxic symptoms, we are not actually poisoned

11. Exposure is defined as:
Actual or suspected contact with any substance which has been ingested, inhaled, absorbed, applied to, or injected into the body, regardless of toxicity or clinical manifestation.
Poisonings happen when the exposure results in an adverse health reaction; when a substance interferes with normal body functions after it is swallowed, inhaled, injected, or absorbed.

12. What is Response?
Change from normal state – could be molecular, cellular, organ, or organism level……the symptoms
The degree and spectra of responses depend upon the dose and the organism
Immediate vs. Delayed (carcinogenic)
Reversible vs. Irreversible (liver vs. brain, teratogenic effect)
Local vs. Systemic
Graded vs. Quantal……degrees of the same damage vs. all or none
Allergic Reactions & Idiosyncratic Reactions….ADRs
Idiosyncratic drug reactions, also known as type B reactions, are drug reactions that occur rarely and unpredictably amongst the population

13. Dose The amount of chemical entering the body
This is usually given as:
mg of chemical / kg of body weight = mg/kg
The dose is dependent upon:
The environmental concentration
The exposure pathway
The length of exposure
The frequency of exposure
The properties of the toxicant

14. i.v > inhalation > i.p > i.m > oral > topical
Exposure: Pathways
Routes and Sites of Exposure:
Ingestion (GIT), (first pass effect)
Ex. Lidocaine and Verapamil (antiarrhythmic drugs)
Inhalation (Lungs): rapid absorption, because of large alveolar surface area
Dermal/Topical (Skin), absorption varies with area of application and drug formulation, but usually absorption is slower than other routes
Injection
Intravenous, intramuscular, intraperitoneal
Typical response of Routes and Sites of Exposure:
i.v > inhalation > i.p > i.m > oral > topical
Intraperitoneal injection or IP injection is the injection of a substance into the peritoneum (body cavity).

15. Exposure: Duration
Toxicologists usually divide the exposure of experimental animals to chemicals into 4 categories……:
Acute
< 24hr
Usually 1 exposure
Sub-acute
1 month
Repeated exposure
Sub-chronic
1-3 months
Chronic
> 3 months
Lethal injection is the practice of killing a person using a lethal dose of drugs administered intravenously. Two methods of lethal injection exist today, one using a three-drug protocol and another using one large dose of a barbiturate.
At the warden's signal, the execution chamber is exposed to witnesses in an adjoining room, and in states that use the three-drug protocol the inmate is injected with sodium thiopental or pentobarbital, anesthetics intended to put the inmate to sleep. Presumably after a member of the intravenous team determines the inmate is sufficiently unconscious, he is then injected with pancuronium bromide, which paralyzes the entire muscle system and stops the inmate's breathing. In most cases, the inmate's consciousness is again checked, and finally potassium chloride stops his heart. In ideal circumstances, death results from anesthetic overdose and respiratory and cardiac arrest while the condemned person is unconscious
Over time, the amount of chemical in the body can build up, it can redistribute, or it can overcome repair and removal mechanisms
Lethal injection by capital punishment…..

16. Exposure = Intensity x Frequency x Duration
The other time-related factor that is important in the temporal characterization of repeated exposures is the frequency of exposure
Exposure = Intensity x Frequency x Duration
Exposure = How much x How often x How long

17. Dose Response Relationship
The magnitude of drug effect depends on the drug concentration at the receptor site, which is in turn determined by the dose of drug administered and by factors of the drug pharmacokinetic profile
There is a graded dose-response relationship in each individual and a quantal dose-response relationship in a population

18. Graded-dose response relationship
The response to a drug is a graded effect, meaning that the measured effect is continuous over a range of doses
Graded dose response curves are constructed by plotting the magnitude of the response against increasing doses of a drug (or log dose)

19. Dose-Response Relationship
As the dose of a toxicant increases, so does the response
Steep curve….relative small dose changes cause large response changes

20. Graded-dose response relationship
Two important properties of drugs can be determined by the graded dose response curves:
Potency
Maximal toxicity

21. ‘U’ Shape of the Dose-Response Curve

22. Quantal-dose response relationship
The quantal (all or none) dose-effect curve often characterizes the distribution of responses to different doses in a population of individual organisms
Median toxic dose(TD50): the dose at which 50% of individuals/population exhibit a particular toxic effect
If the toxic effect is death of the animal, a median lethal dose (LD50) may be experimentally defined
Median effective dose (ED50) is the dose that produces a quantal effect (all or nothing) in 50% of the population that takes it

23. LD50
The dose of chemical required to produce death in 50% of the organism exposed to it
LD50 is not an absolute description of the compound toxicity in all individuals…..Variations
it’s possible to take more than the lethal dose and live, and take less of the lethal dose and die.
the LDLo (Lethal Dose Low) is the lowest dose known to have resulted in fatality in testing, whilst the LD100 (Lethal Dose 100%) is the dose at which 100% of the test subjects are killed.

24. Quantal-dose response relationship
No. of individuals
Resistant
Hyper susceptible
Majority
Sever Response
Mild Response
Dose or log dose

25. Toxicity rating chart Rating Oral Lethal Dose Partially non toxic
>15 g/kg
Slightly toxic
5-15 g/kg
Moderately toxic
0.5-5 g/kg
Very toxic
mg/kg
Extremely toxic
5-50 mg/kg
Super toxic
<5 mg/kg

26. Assumptions in Deriving the Dose-Response Relationship
Confirms that a chemical is responsible for a particular effect
Establishes the lowest dose for which an effect occurs – threshold effect (µg’s….g’s)
Individuals vary in their response to a certain dose of xenobiotic
The magnitude of the response is related to the dose………!!!!!

27. !!!……Molecular Target Concept Agonist Antagonist

28. Toxicodynamics & Kinetics

29. Toxicodynamics
Toxicodynamics refers to the molecular, biochemical, and physiological effects of toxicants or their metabolites in biological systems
These effects are result of the interaction of the biologically effective dose of the ultimate (active) form of the toxicant with a molecular target

30. Toxicokinetics: Disposition (ADME)
Toxicokinetics is the quantitation of the time course of toxicants in the body during the processes of absorption, distribution, biotransformation, and excretion or clearance of toxicants
In other words, toxicokinetics is a reflection of how the body handles toxicants as indicated by the plasma concentration of that xenobiotic at various time points
The end result of these toxicokinetic processes is a biologically toxic concentration of the toxicant/s
Toxicokinetics is the quantitation of the time course of toxicants in the body during the processes of absorption, distribution, biotransformation, and excretion or clearance of toxicants. In other words, toxicokinetics is a reflection of how the body handles toxicants as indicated by the plasma concentration of that xenobiotic at various time points
The end result of these toxicokinetic processes is a biologically effective dose of the toxicant