General Toxicology: Basic Concepts

General Toxicology Study Notes

• Toxicology is "the science of poisons" (toxicon means poison in Greek).
• Toxicology is the study of adverse effects of chemical, physical, or biological agents on living organisms and the ecosystem, including prevention and mitigation.

Other concepts

• Toxicant, toxic agent, and toxic substance are broad terms referring to toxic substances.
• Poison is sometimes used synonymously with the above or to refer to substances used intentionally to cause harm.
• Toxin refers to a toxic substance produced by living organisms, such as bacteria, plants, or fungi.
• Venom is specifically used for toxic complex chemical compounds produced by animals.
• Xenobiotic, is a substance foreign to the body and means a substance external to the body.
• Water can be toxic depending on the amount and route of exposure.

Toxicology history

• The prehistoric recognition poisonous plants and animals was associated with hunting and collecting food.
• 1500 BC: first written records on opium's toxic properties and substances in arrows and metals.
• Moses Maimonides, a Jewish philosopher, wrote The Treatise on Poisons and their Antidotes which covered snake and rabid dog bites, scorpion and insect stings, food and mineral poisons, plus remedies.
• Paracelsus (1494-1541), considered the "father" of toxicology, stated, “All things are poison, and nothing is without poison; the dose alone makes a thing not poison".
• He created two pillars of toxicology with the concept of poison/toxicant and the idea of the dose-responses.
• LD50 (Lethal Dose 50%) is a standard toxicology measure and represents the dose of a substance that kills 50% of test population.
• Mathieu Joseph Bonaventure Orfila (1787-1853), a Spanish chemist and toxicologist was also the founder of toxicology.
• Orfila experimented, varying the amount of poison/dose (such as arsenic) in dogs administering, and tested antidotes.
• Greater understanding of the effects of toxic substances at cellular and molecular levels began with the discovery of DNA in the 20th and 21st centuries

Toxicology areas

• Descriptive Toxicology: measures toxic effects in living organisms.
• Analytical Toxicology: detects, identifies, and measures toxins in biological and environmental samples.
• Regulatory Toxicology: ensures safety standards and regulations for chemicals and drugs.
• Mechanistic Toxicology: studies how toxins cause harm at the cellular and molecular level.
• Clinical Toxicology: diagnoses and treats poisoning in animals and humans.
• Forensic Toxicology: deals with detecting toxins in legal cases.
• Occupational Toxicology: studies workplace exposure to toxins.
• Environmental Toxicology: examines how pollutants affect ecosystems, animals, and humans.
• Veterinary Toxicology: examines the effects and treatments of poisoning in animals.

Dose

• A dose is the amount of a substance administered at one time.

Exposure

• To characterize exposure to xenobiotics, consider amount/dose, number of doses, routes/sites, and duration/frequency.
• Xenobiotics are substances entering the body from the outside that can potentially affect it.

Routes and sites of exposure

• The main administration routes are GI tract (ingestion), lungs (inhalation), and skin (topical/percutaneous/dermal).
• More rapid bloodstream routes: inhalation > intraperitoneal > IM > SC > oral > dermal

Duration and frequency of exposure

• Acute exposure to a chemical lasts less than 24 hours, possibly with repeated exposures.
• Subacute exposure is repeated exposure to a chemical for one month or less.
• Subchronic exposure is repeated exposure to a chemical for 1-3 months.
• Chronic exposure is repeated exposure for more than 3 months.

Single vs. repeated doses

• The rate of elimination is an important aspect to consider in many chemicals (pharmaceutical drugs) for accumulative phenomena and toxic responses.

Dose-response relationship

• Correlative relationship between exposure characteristics and toxic effects/responses.
• Generally, higher the dose the more severe the response.
• Data originates from experimental animal, human clinical, or cell studies.
• It allows for the determination of causality (confirmation that substance induced toxic effects).
• Also threshold effect (lowest dose having an induced effect), and slope for rate of injury development.
• A steep slope indicates higher body sensitivity to a substance's dose changes.
• With a steep slope, even small dose increases will cause big effects.

Dose-response relationship - threshold effect

• There is some dose with zero probability of an individual responding called the threshold.
• Identification depends on particular response measured, the sensitivity of the measurement, and the number of subjects studied.
• Acute toxicological responses are associated with thresholds.
• Chronic toxicological responses, especially carcinogenic, are less well defined.

Dose-response relationship - slope

• A curve with a steep slope indicates the chemical has a high potency, or toxic strength, compared to other chemicals.
• High potency means that the chemical can cause a strong effect at a lower dose.

Individual dose-response relationship

• Individual dose-response relationships relates to varying doses of chemical within individual organism.
• There is a continuous effect that the scientist measures over a range of doses.
• The response increases gradually as the dose increases

Quantal dose-response relationship

• Characterizes the distribution of individual responses to different doses in a population of organisms.
• Describes how populations react to different doses and shows all or nothing effects.

Effective dose

• An effective dose is a dose-response curve.
• Effective Doses (EDs) indicate substance effectiveness.
• It normally refers to a beneficial effect, such as pain relief (pharmacology).
• However, can relate to harmful effect, such as in paralysis (toxicology).
• The dose-response curve is a graphical way to show relationship between dose and effect (beneficial or harmful).
• In pharmacology, the beneficial effects (like pain relief) increase. In toxicology, harmful effects (like paralysis) increase.

Effective dose and toxic dose

• Effective Doses (EDs) refers to a beneficial effect in toxic and effective doses for drugs.
• Toxic Doses (TDs) are used to indicate doses that cause adverse toxic effects.

Interpretation of effective/toxic doses relationship

• Dose effective for 50% of population (ED50) doesn't cause toxicity if before the threshold effect.
• 90% effective dose (ED90) may cause small, detectable toxicity (perhaps 1%).
• The Therapeutic Index (TI) is used to compare a pharmaceutical agent's therapeutically effective dose to its toxic dose.
• Higher TIs indicate safer drugs because there is a greater difference between the dose causing harm compared to the effects. T - I =toxic dose/effective dose.
• Margin of Safety (MOS) is the ratio of the toxic dose to 1% of the population (TD01) to the dose that is 99% effective to the population (ED99).
• M - O - S=toxic dose/effective dose
• Margin of Safety and Therapeutic Index can help easily see that the first drug will be safer than the second

Effective dose, toxic dose and deficient dose

• Substances needed for physiological function and survival such vitamins has a U-shaped responses as they are required for survival depending on dose amount.
• Very low doses lead to adverse effects.
• An increase up to some dose ensures the deficiency no longer exists.
• Excessive doses lead to adverse effects and can be a toxicity.

Hormesis

• Some toxic substances at low doses may have beneficial or stimulatory effects that becomes adverse at higher doses.
• Examples includes alcohol which shows cardiovascular benefits at low dose.

Dose descriptors

• Used to identify relationships between specific effects of chemical substances and site.
• The dose-response describes how the substance's effects on the body change depending on the dose.
• Includes LC50, LD50, NOAEL, NOAEC, TD25, ED50, EC50, NOEC, TD50, etc.

LD50

• LD50 (Lethal Dose 50%) is a statistically derived dose at which 50% of the test animals are expected to die.
• Units of LD50 and LC50 are for mg of substance per per kg of body weight per day.
• LC50: mg/L is the estimated air concentration of a substance through inhalation
• A lower LD50/LC50 value indicates a higher acute toxicity.

NOAEL and LOAEL

• Results from research studies establish the highest nontoxic and lowest doses at which toxic and adverse effects happen.
• No Observed Adverse Effect Level (NOAEL) and Lowest Observed Adverse Effect Level (LOAEL).

NOAEL

• NOAEL is the highest exposure level without biologically significant increases in adverse effect frequency or severity between the exposed population and its control.
• Important as they derive threshold dose estimates for humans.
• Higher NOAEL indicates a lower toxicity.

LOAEL

• LOAEL is the lowest exposure level with biologically significant increases in frequency or severity of adverse effects between the exposed population and its control.
• LOAEL is also used to derive safety exposure dose in humans when NOAEL cannot be identified.
• Higher LOAEL indicates lower toxicity

Toxicity

• Qualities or degrees of being toxic or poisonous and represents biological charge induction.
• Many chemicals distribute in the body and often affect just specific target organs.
• Target organs and effects varying dosage and route of exposure Toxicants might be toxic themselves or require metabolism before they cause toxicity.

Toxicity classification

• Immediate toxicity leads to toxic effects that occur or develop rapidly after a single administration.
• Also delayed which causes toxic effects after the lapse of some time.
• This refers especially to carcinogenic effects from chemicals 20 to 30 years after the initial exposure.
• Toxicity may be reversible (tissue has ability regenerating) vs Irreversible (CNS with no cells able dividing or replacing). Toxicity may be local (contact exposure) vs systemic (absorption).

Factors influencing toxicity

• Toxicity the form and innate chemical activity as well as dosage especially dose time relations.
• Exposure route, the route of absorption like with or without a barrier.
• Individual factors like species, age, gender, health, nutritional status, and the circadian rhythms.
• Interactions of those chemicals with other chemicals.

Factors influencing toxicity - form/innate chemicals

• The form of a substance shows effect toxicity for metallic elements aka heavy metals.
• Example: toxicity of mercury differs from methyl mercury.
• Dosage/time relationship - Cr3+ relatively nontoxic, Cr6+ lead to nasal and lung cancer.

Factors influencing toxicity - exposure route

• Inhaled toxicants immediately circulation general blood for rapid toxicant distribution and intake to liver.
• Ingrestred chemicals detoxified by distribution first liver.

Factors influencing toxicity - interations of chemicals

• The presence of other chemicals can shows Decrease toxicity (Antagonism), Add/ or Increase to toxicity.
• 3+1=2 means Antagonism while 3+2=5 meaning Additivity
• 2+2=20 means Synergism and 0+2 = 10 which showing is potentiation.

Toxicokinetics

• Study of "how is substance in the body and what is doing".
• Compared to what that they body should to have a effect.
• This means quantitative distribution exogenous for chemicals on its final disposition.
• Absorption has enter
• Distribution is moves
• Biostransformation is transform
• Excretion is leaving body The substance will goes to excretion

Toxicokinetics vs toxicity

• Factors determine harmful effects that substance for the absorption and distribution in specific volume of concentration and entry.
• All ability storage and the body status.
• Example - highly can harm with higher absorption with less toxicity.
• Absorption are poorly with toxic as high is greatly harm. The substance transfer then more toxicity with less toxicity

Absorption

• Vary by special route of chaminals.
• For skin, soil, respiratory, dose.
• If there is a direct body with absorb or internal dose. Important factor for this that the site of contact through them.
• Cell membranes that allow in or out and pass though.
• barriers are defended through entrance such as tightly compaction which mean it won't pass.

Absorption - cell membranes

• The move easy are difficult and impossible which that body use one method or two; simple diffusion or energy

1. No needs transport with their molecular energy.
2. Move a gradient of transport protein baring in the transport system.
3. The will create a vesticle pinocytosis are a cell of eating through it.

• lipid size are effect with membrane through water system.

Absorption - GI tract

• It be must cross membrane.
• toxic effect is affect absorption is specific for site with depend the all .
• That the specific time.

Absorption - upper reapiratoey

• Amount depends solubility. That pulmonary for is very short to go on sac for the lungs mucus.
• There are basic regions for respitorty in
• Nasopharygea, trachel, or pullminity.
• Gas is in vapor

Absorption - other area

• if have area, so the agent enters by this route.
• If the agent goes up, have some area.

Absorption - dermal route

It is complex that serve as most xenobiotic.

• The have main thins that is dermis, epdermis, and subcutenous.

• Fat soluble to the subetance. The thickness affect the system is it is more affect some body parts.

• Dermis has the lowers for that it is selective as is enters th

Distribution -general

• Process after a absorbed
• Chemials for in or for the fluids around organ through specific blood and lymptic.
• The have other fluid is intracellular

Distribution- volume and binding

• Volume in distribution VD in to the fluid total that toxicant in.
• Distributuon that stay plasmy, the VD to it as well.
• Toxicant who is in biotransform a and elimation that toxilogists that determine it Formula :

V = mass D plasma concentrations- Volume on distribution VD in to the fluid, total that toxicant in

Distribution- organs

• Once it happens
• the storage on blod.
• May for interact/ biotransform with cell.
• the some areas that slower has the volume, barriers, Biotransform effectiveness and the immediate elimnations

Meta bolism and biotransfprms

• bio a by change of sustanc.
• is is neceasry survive through is bio or detoxification
• they all importnant and liver.
• the kidneys/ lungs skin.testes a s are low capacity

Phase on Biotransfomation

• that modify structure or conjuate substance
• enzymes have

Bitransfprm and the detoxification through biovacativation

• occurs can be high of dose.
• paracentamol . have example for this

-the

Elimination

This bio

• the body it that that
• The polars high to for
• The primarty -urina .gastrointertinal system and respitatory

Exretion - utinary system

• That substance. It is the urine can show alkalinies or aid
• it ha that active mechanism are two systems. acis. ,bacis., lipid to city
• The GI system. through enzyme.. The 300 more that they the has .

the other routes.

Toxicodynamics

It is the process of reaction.

• There has all level from the macro to the tissue . * function of this is affect structure

multiple are that with diseases such genom, proteins

Toxicology is the study of poisons and their adverse effects on living organisms. Key terms include toxicant, toxin, venom, and xenobiotic. This covers the historical recognition of poisonous substances.