Poisons and DrugsPoisons and Drugs

Prof. Monzir S. Abdel-LatifProf. Monzir S. Abdel-LatifChemistry DepartmentChemistry Department

Islamic University of GazaIslamic University of Gazahttp://www.monzir-pal.nethttp://www.monzir-pal.net

SyllabusSyllabus

In this course, it is anticipated to cover the following topics:In this course, it is anticipated to cover the following topics:1.1. Introduction to ToxicologyIntroduction to Toxicology2.2. Epidemiological StudiesEpidemiological Studies3.3. Toxicodynamics and ToxicokineticsToxicodynamics and Toxicokinetics4.4. Toxicokinetics ...... ContinuedToxicokinetics ...... Continued5.5. Toxicokinetics ... continuedToxicokinetics ... continued6.6. Risk Assessment and ManagementRisk Assessment and Management7.7. Review of Analytical MethodsReview of Analytical Methods8.8. Drug Testing Methodologies and Possible Pitfalls Drug Testing Methodologies and Possible Pitfalls

Methods of AnalysisMethods of Analysis1.1. Gas ChromatographyGas Chromatography2.2. Liquid chromatographyLiquid chromatography3.3. Mass SpectrometryMass Spectrometry4.4. Hyphenated TechniquesHyphenated Techniques5.5. AAS and AESAAS and AES6.6. Spectrophotometry and FluorometrySpectrophotometry and Fluorometry Sample PreparationSample Preparation Classes of drugs and poisonsClasses of drugs and poisons1.1. According to site of actionAccording to site of action2.2. Grouping of drugsGrouping of drugs

Drug Classification: Drug Classification: 9.9. Amphetamines Amphetamines 10.10. Lysergic acid and LSDLysergic acid and LSD11.11. Other Hallucination DrugsOther Hallucination Drugs12.12. CannabisCannabis13.13. Opiates and CocaineOpiates and Cocaine14.14. Therapeutic Drug MonitoringTherapeutic Drug Monitoring15.15. PesticidesPesticides16.16. Illicit Drugs Analyzed by the Forensic Illicit Drugs Analyzed by the Forensic

Lab in Gaza Lab in Gaza

We will follow presentation chapters from several We will follow presentation chapters from several textbooks including “Fundamantal Toxicology” by John textbooks including “Fundamantal Toxicology” by John Duffus and Howard Worth, published by RSC in 2006, Duffus and Howard Worth, published by RSC in 2006, Poisoning and Toxicology handbook, 4Poisoning and Toxicology handbook, 4 thth Ed., A Guide to Ed., A Guide to Practical Toxicology, 2Practical Toxicology, 2ndnd Ed, Woolley, Toxicological Ed, Woolley, Toxicological Chemistry and Biochemistry, 3Chemistry and Biochemistry, 3rdrd Ed., as well as others . Ed., as well as others .

However, other books in Instrumental Analysis and However, other books in Instrumental Analysis and related research papers will be found very helpful.related research papers will be found very helpful.

I’ll try to maintain a web page for the course and regularly I’ll try to maintain a web page for the course and regularly post reading material for you to look at. post reading material for you to look at.

Introduction to ToxicologyIntroduction to Toxicology

Toxicology is the fundamental science of poisons.Toxicology is the fundamental science of poisons. A poison is a substance that can cause severe injury or A poison is a substance that can cause severe injury or

death as a result of interaction with living tissue.death as a result of interaction with living tissue. Therefore, in principle, all chemicals can be considered as Therefore, in principle, all chemicals can be considered as

potential poisons causing injury or death upon excessive potential poisons causing injury or death upon excessive exposure. At the same time all chemicals can be regarded exposure. At the same time all chemicals can be regarded as safe if exposure to chemicals was kept below a tolerable as safe if exposure to chemicals was kept below a tolerable limit. limit.

Exposure to toxinsExposure to toxinsExposure is a function of the following factors:Exposure is a function of the following factors: Amount or concentration of the target chemicalAmount or concentration of the target chemical Time of interaction of the chemical with the target organTime of interaction of the chemical with the target organ Frequency of interaction of the chemical with the target Frequency of interaction of the chemical with the target

organorgan Organ exposedOrgan exposed For humans, age and health of the subject are also For humans, age and health of the subject are also

important factorsimportant factorsFor highly toxic chemicals, the tolerable exposure is close to For highly toxic chemicals, the tolerable exposure is close to

zerozero

Determination of tolerable exposureDetermination of tolerable exposure

In fact, this constitutes a problem since we do need In fact, this constitutes a problem since we do need reliable data relating exposure to injury or adverse reliable data relating exposure to injury or adverse effect in humans.effect in humans.

Unfortunately, what can be considered as an injury Unfortunately, what can be considered as an injury or an adverse effect is not well defined and or an adverse effect is not well defined and debatable. We will look at this problem laterdebatable. We will look at this problem later

Adverse effectsAdverse effects

An adverse effect can be defined as an abnormal, An adverse effect can be defined as an abnormal, undesirable, or harmful change of people or undesirable, or harmful change of people or organs following exposure to the potentially organs following exposure to the potentially toxic substancetoxic substance

Although the ultimate adverse effect is death, the Although the ultimate adverse effect is death, the following are definite adverse effects:following are definite adverse effects:

Altered food consumptionAltered food consumptionAltered body or organ weightAltered body or organ weightAltered enzyme or hormone levels, ..etcAltered enzyme or hormone levels, ..etc

Harmful effectsHarmful effects

An effect is considered harmful if it causes a functional An effect is considered harmful if it causes a functional damage to an organ, irreversible change in homeostasis or damage to an organ, irreversible change in homeostasis or increased susceptibility to chemical or biological stress increased susceptibility to chemical or biological stress including infectious diseases.including infectious diseases.

One should consider the degree of alteration from One should consider the degree of alteration from normality and the relation of the altered property to the normality and the relation of the altered property to the total well-being of the persontotal well-being of the person

In some cases, a person can adapt to the irreversible In some cases, a person can adapt to the irreversible alteration and practice normal lifealteration and practice normal life

In some cases of immune reactions In some cases of immune reactions leading to allergy:leading to allergy:

The first exposure may not cause an adverse effect The first exposure may not cause an adverse effect of allergy, however, it may sensitize the organism of allergy, however, it may sensitize the organism to respond adversely (badly) to future exposures to respond adversely (badly) to future exposures even at lower levelseven at lower levels

Amount of exposureAmount of exposure

The amount of exposure to a chemical that causes The amount of exposure to a chemical that causes injury varies over a very wide range depending on injury varies over a very wide range depending on the type of chemical and its form (liquid, solid, or the type of chemical and its form (liquid, solid, or gas)gas)

This can be quantified using the median lethal dose This can be quantified using the median lethal dose (LD(LD5050) concept or lethal concentration LC) concept or lethal concentration LC5050

Median Lethal Dose (LDMedian Lethal Dose (LD5050), mg toxin/kg ), mg toxin/kg

body weightbody weight LDLD50 50 is a statistically derived single dose of a is a statistically derived single dose of a

chemical that can be expected to cause the death of chemical that can be expected to cause the death of 50% of organisms of a given population, under a 50% of organisms of a given population, under a defined set of experimental conditions.defined set of experimental conditions.

LDLD5050‘s when reported for human beings are ‘s when reported for human beings are obtained by extrapolation from studies on obtained by extrapolation from studies on mammals, or observations following accidental or mammals, or observations following accidental or suicidal exposures. suicidal exposures.

The LDThe LD5050 is used to classify and compare toxicity of is used to classify and compare toxicity of

chemicals, although it is of limited merits. For example, chemicals, although it is of limited merits. For example, the LDthe LD5050 classification orally to rats are: classification orally to rats are:

Very toxicVery toxic less than 25 mg/kgless than 25 mg/kg ToxicToxic from 25 -199 mg/kgfrom 25 -199 mg/kg HarmfulHarmful from 200 - 2000 mg/kgfrom 200 - 2000 mg/kg

However, it is not convincing to label a substance as toxic However, it is not convincing to label a substance as toxic because its LDbecause its LD5050 is 199, while labeling another as harmful is 199, while labeling another as harmful

since its LDsince its LD5050 is 200. That is why the LD is 200. That is why the LD5050 values need values need

more refinements.more refinements.

In addition, when using LDIn addition, when using LD5050 values, there is no values, there is no

simple relationship between lethality and sub lethal simple relationship between lethality and sub lethal toxic effects.toxic effects.

In other words also, it is not informative to what is In other words also, it is not informative to what is the minimum dose that can be lethal, and thus no the minimum dose that can be lethal, and thus no indication of what can be considered a safe indication of what can be considered a safe exposure level.exposure level.

Toxicity versus RiskToxicity versus Risk

With regards to chemical safety, risk assessment With regards to chemical safety, risk assessment can be more important than actual toxicity of can be more important than actual toxicity of chemicals. chemicals.

Risk can be regarded as the probability that a Risk can be regarded as the probability that a substance would impart unacceptable harm or substance would impart unacceptable harm or unacceptable effects to an organ or to ecosystems unacceptable effects to an organ or to ecosystems upon exposure.upon exposure.

SafetySafety

It is possible to define safety as the practical certainty that It is possible to define safety as the practical certainty that injury will not (high probability) result from exposure to a injury will not (high probability) result from exposure to a hazard under defined conditions.hazard under defined conditions.

Practical certainty is a numerically specified low risk (or Practical certainty is a numerically specified low risk (or socially acceptable risk). socially acceptable risk).

Assessment of risk depends on scientific data, but Assessment of risk depends on scientific data, but acceptability is influenced by social, economic, political acceptability is influenced by social, economic, political and benefits arising from a chemical or a process.and benefits arising from a chemical or a process.

Uncertainty (safety) factorsUncertainty (safety) factors

A threshold of exposure above which an adverse A threshold of exposure above which an adverse effect can occur and below which no such effect is effect can occur and below which no such effect is observed, is obtained from available data. observed, is obtained from available data.

The threshold of exposure is then divided by a The threshold of exposure is then divided by a factor (uncertainty or safety factor) to lower it to a factor (uncertainty or safety factor) to lower it to a new value that toxicologists can regard as safe new value that toxicologists can regard as safe beyond doubt.beyond doubt.

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

Safety Factor Selection:Safety Factor Selection:1.1. An uncertainty (safety) factor of 10 is used when An uncertainty (safety) factor of 10 is used when

valid human data based on chronic exposure is valid human data based on chronic exposure is availableavailable

2.2. An uncertainty (safety) factor of 100 is used An uncertainty (safety) factor of 100 is used when human data is inconclusive or limited to when human data is inconclusive or limited to acute exposure, but reliable data on animals is acute exposure, but reliable data on animals is availableavailable

3.3. An uncertainty (safety) factor of 1000 is used An uncertainty (safety) factor of 1000 is used when no human data is available and when no human data is available and experimental animal data is limited experimental animal data is limited

Exposure to potentially toxic substancesExposure to potentially toxic substances

Toxins can cause injury when they reach Toxins can cause injury when they reach sensitive parts of an organism at a sufficiently sensitive parts of an organism at a sufficiently high concentration.high concentration.

Exposure can occur through:Exposure can occur through:

1.1. Skin (dermal or percutaneous) AbsorptionSkin (dermal or percutaneous) Absorption

2.2. InhalationInhalation

3.3. IngestionIngestion

Skin absorptionSkin absorption Among the chemicals that are absorbed through the skin Among the chemicals that are absorbed through the skin

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

InhalationInhalation

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

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

Some insoluble particles such as asbestos, coal dust and Some insoluble particles such as asbestos, coal dust and silica dust will readily cause fibrosis of the lungsilica dust will readily cause fibrosis of the lung

IngestionIngestion

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

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