Objectives of this lecture are to: Determine characteristics of exposure.

1. General ToxicologyGeneral Considerations in Toxicology (II)Lec. 24th Year2018-2019College of Pharmacy/University of MustansiriyahDepartment of Pharmacology & ToxicologyLecturer Rua Abbas Al-Hamdy

2. Objectives of this lecture are to: • Determine characteristics of exposure. • Determine the routes of exposure to toxic agents. • Explain the categories of duration of exposure in experimental animals & human beings. • Determine the effect of frequency of exposure on toxic effects. • Determine host & environmental factors affecting toxicity.

3. Characteristics of exposure: • Toxic effects in a biological system are not produced by a chemical agent unless that agent or its metabolic breakdown (biotransformation) products: • reach appropriate sites in the body, • at a concentration &/or a length of time sufficient to produce a toxic manifestation.

4. Whether a toxic response occurs is dependent on: • the chemical & physical properties of the agent, • the exposure situation, • how the agent is metabolized by the system, • & the overall susceptibility of the biological system or subject.

5. Route & site of exposure: • The major routes (pathways) by which toxic agents gain access to the body are: • the gastrointestinal tract (ingestion), • lungs (inhalation), • skin (topical, percutaneous, or dermal), • & other parenteral (other than intestinal canal) routes.

6. Toxic agents generally produce the greatest effect & the most rapid response when given directly into the bloodstream (the intravenous route). • An approximate descending order of effectiveness for the other routes would be: • inhalation, • intraperitoneal, • subcutaneous, • intramuscular, • intradermal, • oral, • & dermal

7. The route of administration can influence the toxicity of agents. For example, an agent that acts on the CNS, but is efficiently detoxified in the liver, would be expected to be less toxic when given orally than when inhaled.

8. Duration & frequency of exposure: • Duration of exposure: • Toxicologists usually divide the exposure of experimental animals to chemicals into four categories: • Acute exposure is defined as exposure to a chemical for less than 24 h. • Subacute exposure: refers to repeated exposure to a chemical for 1 month or less, • Subchronic exposure: for 1 to 3 months, • & chronic exposure: for more than 3 months.

9. In human exposure situations, the frequency & duration of exposure are usually not as clearly defined as in controlled animal studies. • Workplace or environmental exposures may be described as acute (occurring from a single incident or episode) • Subchronic (occurring repeatedly over several weeks or months), • Chronic (occurring repeatedly for many months or years).

10. Frequency of exposure: • The other time-related factor that is important in the temporal characterization of repeated exposures is the frequency of exposure. • The relationship between elimination rate & frequency of exposure is shown in Figure 1.

11. Figure 1. Diagrammatic view of the relationship between dose and concentration at the target site under different conditions of dose frequency and elimination rate. Line A. A chemical with very slow elimination (e.g., half -life of 1 year). Line B. A chemical with a rate of elimination equal to frequency of dosing (e.g., 1 day). Line C. Rate of elimination faster than the dosing frequency (e.g., 5 h). Purple shaded area is representative of the concentration of chemical at the target site necessary to elicit a toxic response.

12. The important consideration, is whether the interval between doses is sufficient to allow for complete repair of tissue damage. • Chronic toxic effects may occur, if: • the chemical accumulates in the biological system (rate of absorption exceeds the rate of biotransformation and/or excretion), • if it produces irreversible toxic effects, • or if there is insufficient time for the system to recover from the toxic damage within the exposure frequency interval.

13. Host & environmental factors affecting toxicity: • Among factors that influence toxicity are: • Host factors, & • Environmental factors.

14. Host factors: 1. Genetics 2. Gender 3. State of health 4. Age & maturity 5. Nutritional state & dietary factors

15. Genetics: • Pharmacogenetics describes the differences in an individual's response to drugs & chemicals that are related hereditary influences due to genetic polymorphism. • Examples: • Succinylcholine is a skeletal muscle relaxant that is often administered during the induction of general anesthesia. • The toxicologic problem arises because of the presence of an atypical pseudocholinesterase in a segment of the population.

16. This would predispose them to a prolonged & life-threatening paralysis of respiratory muscles because the initial detoxifying step in succinylcholine metabolism is hampered.

17. Another example: individuals with erythrocytic glucose 6-phosphate dehydrogenase (G6PD) deficiency are at special risk of toxicity to oxidizing agents, such as naphthalene, & sulfonamides. • When red blood cells (RBCs) are exposed to oxidizing agents, reduced glutathione (GSH) protects them from cellular injury & hemolysis.

18. Regeneration of glutathione to its reduced form (GSH) again requires reduced nicotinamide adenine dinucleotide phosphate (NADPH) & glutathione reductase (Figure 1). Obviously, when G6PD is deficient, RBCs are unable to generate NADPH &, therefore, GSH function is impaired.

19. Figure 1. The role of glucose 6-phosphate dehydrogenase (G6PD) in protection against oxidizing agents.

20. Gender: • Toxicologists are beginning to understand the differences in drug & chemical responses between men & women. • Examples: • Some studies report a sex-related difference in absorption of erythromycin, resulting in less drug being absorbed by women after oral administration.

21. Another example, bioavailability of ethanol is greater in women than in men. This is associated with decreased gastric alcohol dehydrogenase activity in women, which contributes to reduced gastric oxidation of ethanol.

22. State of health: • The presence of hepatic or renal disease may significantly affect the pharmacokinetics & outcome of exposure to a particular toxicant. • Disease states that cause diarrhea or constipation may decrease or increase the time of contact between chemical & absorptive sites &, thus, reduce or enhance absorption.

23. Age & maturity: • Anticipated toxic effects are based on individuals who are either too young or too old. • The majority of accidental poisonings in fact occurs in persons less than 5 years of age. • An example of the effect of age & maturity on toxicity is the chloramphenicol-induced gray baby syndrome occurring in infants.

24. Chloramphenicol is normally metabolized & excreted largely as a glucuronide conjugate. Infants are unable to metabolize chloramphenicol because their hepatic microsomal enzyme system was not fully developed. Consequently, toxic concentrations of chloramphenicol would be reached after only a few doses.

25. In geriatric patients, the toxic effects of drugs & chemicals may be complicated by decreased hepatic & renal function. These factors may alter the metabolism or excretion of toxic agents.

26. Nutritional state & dietary factors: • In general, higher blood concentrations are achieved when drugs are taken on an empty as opposed to a full stomach. • Certain food may significantly increase or decrease drug absorption. For example, calcium may bind to tetracycline & reduce its absorption.

27. Some foods can actually increase the toxicity of certain drugs by means other than influencing their absorption. • An excellent example are those foods that are rich in the pressor amine, tyramine. • If one of these foods is ingested while an individual is taking a monoamine oxidase-inhibiting drug (for example, phenelzine), sever symptoms of hypertensive crisis & even death may occur.

28. Tyramine-containing foods are ordinarily metabolized to a nontoxic substance by monoamine oxidase, which is located within the cells lining the GI tract. Therefore, only a small amount of tyramine is absorbed. • When monoamine oxidase is inhibited, tyramine is not metabolized but absorbed into the blood where it causes toxic pressor activity.

29. Environmental factors: • Temperature • Occupation

30. Temperature: • The response of a biologic system to a toxic agent generally decreased as environmental temperature is lowered, but the duration of overall response may be prolonged. • This is related to a decreased rate of absorption & a lowered rate of metabolic degradation & excretion in colder environments.

31. Occupation: • Persons working in industries where organic compounds, such as chlorinated hydrocarbon pesticides or volatile substances, are used may have an enhanced ability to metabolize drugs & chemicals. • The reason for this is that the chemical's presence in the environment may have caused the induction of liver microsomal enzyme activity.

32. The expected reaction to a toxic agent that is normally detoxified by the liver microsomal enzyme system would be reduced. Of course, the reaction would be greater than normal for those substances metabolized to more toxic forms.