Poisons and Drugs

1. Poisons and Drugs Prof. Monzir S. Abdel-Latif Chemistry Department Islamic University of Gaza http://www.monzir-pal.net

2. Syllabus In this course, it is anticipated to cover the following topics: • Introduction to Toxicology • Epidemiological Studies • Toxicodynamics and Toxicokinetics • Toxicokinetics ...... Continued • Toxicokinetics ... continued • Risk Assessment and Management • Review of Analytical Methods • Drug Testing Methodologies and Possible Pitfalls

3. Methods of Analysis • Gas Chromatography • Liquid chromatography • Mass Spectrometry • Hyphenated Techniques • AAS and AES • Spectrophotometry and Fluorometry • Sample Preparation • Classes of drugs and poisons • According to site of action • Grouping of drugs

4. Drug Classification: • Amphetamines • Lysergic acid and LSD • Other Hallucination Drugs • Cannabis • Opiates and Cocaine • Therapeutic Drug Monitoring • Pesticides • Illicit Drugs Analyzed by the Forensic Lab in Gaza

5. We will follow presentation chapters from several textbooks including “Fundamantal Toxicology” by John Duffus and Howard Worth, published by RSC in 2006, Poisoning and Toxicology handbook, 4th Ed., A Guide to Practical Toxicology, 2nd Ed, Woolley, Toxicological Chemistry and Biochemistry, 3rd Ed., as well as others . • However, other books in Instrumental Analysis and related research papers will be found very helpful. • I’ll try to maintain a web page for the course and regularly post reading material for you to look at.

6. Introduction to Toxicology • Toxicology is the fundamental science of poisons. • A poison is a substance that can cause severe injury or death as a result of interaction with living tissue. • Therefore, in principle, all chemicals can be considered as potential poisons causing injury or death upon excessive exposure. At the same time all chemicals can be regarded as safe if exposure to chemicals was kept below a tolerable limit.

7. Exposure to toxins Exposure is a function of the following factors: • Amount or concentration of the target chemical • Time of interaction of the chemical with the target organ • Frequency of interaction of the chemical with the target organ • Organ exposed • For humans, age and health of the subject are also important factors For highly toxic chemicals, the tolerable exposure is close to zero

8. Determination of tolerable exposure In fact, this constitutes a problem since we do need reliable data relating exposure to injury or adverse effect in humans. Unfortunately, what can be considered as an injury or an adverse effect is not well defined and debatable. We will look at this problem later

9. Adverse effects • An adverse effect can be defined as an abnormal, undesirable, or harmful change of people or organs following exposure to the potentially toxic substance • Although the ultimate adverse effect is death, the following are definite adverse effects: Altered food consumption Altered body or organ weight Altered enzyme or hormone levels, ..etc

10. Harmful effects • An effect is considered harmful if it causes a functional damage to an organ, irreversible change in homeostasis or increased susceptibility to chemical or biological stress including infectious diseases. • One should consider the degree of alteration from normality and the relation of the altered property to the total well-being of the person • In some cases, a person can adapt to the irreversible alteration and practice normal life

11. In some cases of immune reactions leading to allergy: • The first exposure may not cause an adverse effect of allergy, however, it may sensitize the organism to respond adversely (badly) to future exposures even at lower levels

12. Amount of exposure • The amount of exposure to a chemical that causes injury varies over a very wide range depending on the type of chemical and its form (liquid, solid, or gas) • This can be quantified using the median lethal dose (LD50) concept or lethal concentration LC50

13. Median Lethal Dose (LD50), mg toxin/kg body weight • LD50 is a statistically derived single dose of a chemical that can be expected to cause the death of 50% of organisms of a given population, under a defined set of experimental conditions. • LD50‘s when reported for human beings are obtained by extrapolation from studies on mammals, or observations following accidental or suicidal exposures.

15. The LD50 is used to classify and compare toxicity of chemicals, although it is of limited merits. For example, the LD50 classification orally to rats are: • Very toxic less than 25 mg/kg • Toxic from 25 -199 mg/kg • Harmful from 200 - 2000 mg/kg • However, it is not convincing to label a substance as toxic because its LD50 is 199, while labeling another as harmful since its LD50 is 200. That is why the LD50 values need more refinements.

16. In addition, when using LD50 values, there is no simple relationship between lethality and sub lethal toxic effects. • In other words also, it is not informative to what is the minimum dose that can be lethal, and thus no indication of what can be considered a safe exposure level.

17. Toxicity versus Risk • With regards to chemical safety, risk assessment can be more important than actual toxicity of chemicals. • Risk can be regarded as the probability that a substance would impart unacceptable harm or unacceptable effects to an organ or to ecosystems upon exposure.

18. Safety • It is possible to define safety as the practical certainty that injury will not (high probability) result from exposure to a hazard under defined conditions. • Practical certainty is a numerically specified low risk (or socially acceptable risk). • Assessment of risk depends on scientific data, but acceptability is influenced by social, economic, political and benefits arising from a chemical or a process.

19. Uncertainty (safety) factors • A threshold of exposure above which an adverse effect can occur and below which no such effect is observed, is obtained from available data. • The threshold of exposure is then divided by a factor (uncertainty or safety factor) to lower it to a new value that toxicologists can regard as safe beyond doubt.

21. US National Academy of Sciences safe drinking water committee proposed the following guidelines for selecting the safety factors, to be used with no observed effect level (NOEL) data.

22. Safety Factor Selection: • An uncertainty (safety) factor of 10 is used when valid human data based on chronic exposure is available • An uncertainty (safety) factor of 100 is used when human data is inconclusive or limited to acute exposure, but reliable data on animals is available • An uncertainty (safety) factor of 1000 is used when no human data is available and experimental animal data is limited

23. Exposure to potentially toxic substances • Toxins can cause injury when they reach sensitive parts of an organism at a sufficiently high concentration. • Exposure can occur through: • Skin (dermal or percutaneous) Absorption • Inhalation • Ingestion

24. Skin absorption • Among the chemicals that are absorbed through the skin are aniline, hydrogen cyanide, some steroid hormones, organic mercury compounds, nitrobenzene, organophosphate compounds and phenol. Some chemicals, such as phenol or methylmercury chloride, can be lethal if absorbed from a fairly small area (a few square centimeters) of skin. If protective clothing is being worn, it must be remembered that absorption through the skin of any chemical that gets inside the clothing will be even faster than through unprotected skin because the chemical cannot escape and contact is maintained over a longer time.

26. Inhalation Gases and vapors are easily inhaled but inhalation of particles depends upon their size and shape. The smaller the particle, the further into the respiratory tract it can go. Dusts with an effective aerodynamic diameter of between 0.5 and 7 µm can persist in the alveoli and respiratory bronchioles after deposition. Peak retention depends upon the aerodynamic shape but is mainly of those particles with an effective aerodynamic diameter of between 1 and 2 µm.

28. Physical irritation by dust particles or fibers can cause very serious adverse health effects but most effects depend upon the solids being dissolved. Special consideration should be given to asbestos fibers which may lodge in the lung and cause fibrosis and cancer even though they are mostly insoluble and therefore do not act like classical toxicants: care should also be taken in assessing possible harm from man-made mineral fibers that have similar properties. Some insoluble particles such as asbestos, coal dust and silica dust will readily cause fibrosis of the lung

29. Ingestion A chemical may accumulate if absorption exceeds excretion; this is particularly likely with substances that combine a fairly high degree of lipid solubility with chemical stability. Such chemicals are found in the group of persistent organic pollutants (POPS), including several organochlorine pesticides, which are now largely, but not entirely, banned from use

30. Divalent lead ions accumulate in bone where they replace the chemically similar calcium ions. While in the bone, they cause little harm but when bone breaks down, or during pregnancy or illness, the lead ions enter the blood and may poison the person who has accumulated them or, in the case of pregnancy, the unborn child.