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Integrates the knowledge and techniques from most branches of biochemistry, biology, chemistry, genetics, mathematics, medicine, pharmacology, physiology, and physics Applies safety evaluation and RISK ASSESSMENT to the discipline ------------------------------------------ the branch of science concerned with the nature, effects, and detection of poisons. the measurement and analysis of potential toxins, intoxicating or banned substances, and prescription medications present in a person's body.

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Toxicology

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TOXICOLOGY - Marcador

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LEIGHTON DWIGHT OBILLOS

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TOXICOLOGY - Detalles

Niveles:

1) Chapter 1 Visualizar
2) Mechanism of Toxicity Visualizar
3) Carcinogenesis Visualizar
4) TOXIC RESPONSES OF THE RESPIRATORY SYSTEM Visualizar
5) TOXIC RESPONSES OF THE SKIN Visualizar
6) Toxin Effects of Terrestrial Animals Visualizar
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Toxicology

1 First journal of experimental toxicology "__" in 1930 2 response to a tragic CONSEQUENCES OF ACUTE KIDNEY FAILURE after taking SULFANILAMIDE IN GLYCOL SOLUTIONS

1 Archiv fur Toxicologie 2 Copeland Bill in U.S

1 First journal of experimental toxicology "__" in 1930 2 response to a tragic CONSEQUENCES OF ACUTE KIDNEY FAILURE after taking SULFANILAMIDE IN GLYCOL SOLUTIONS

1 Archiv fur Toxicologie 2 Copeland Bill in U.S

Involves estimating quantitavely the potential effects of Human health and environmental insignificance of the various type of chemical exposure

Risk assessment

Trained to examine the nature of effects and assess the probability of their occurrence of different xenobiotic. explore the mechanism by which chemicals produce adverse effects in our biological system or living system such as humans and animals.

Toxicologist

1 First journal of experimental toxicology "__" in 1930 2 response to a tragic CONSEQUENCES OF ACUTE KIDNEY FAILURE after taking SULFANILAMIDE IN GLYCOL SOLUTIONS

1 Archiv fur Toxicologie 2 Copeland Bill in U.S

Chemical compound and it can be drug, pesticides, carcinogen or any chemical compound that is usually FOREIGN TO A LIVING ORGANISM a chemical substance found within an organism that is not naturally produced or expected to be present within the organism

Xenobiotics

1 First journal of experimental toxicology "__" in 1930 2 response to a tragic CONSEQUENCES OF ACUTE KIDNEY FAILURE after taking SULFANILAMIDE IN GLYCOL SOLUTIONS

1 Archiv fur Toxicologie 2 Copeland Bill in U.S

ANTIQUITY 1 Included numerous references to POISONOUS PLANTS in his famous writing DE HISTORIA PLANTARUM 2 Added a number of poisons and clinical toxicology principles pertaining to BIOAVAILABILITY IN THERAPY and OVERDOSAGE

. 1 Theophrastus (370-286 BC) - Student of Aristotle 2 Hippocrates (400 BC)

1 First journal of experimental toxicology "__" in 1930 2 response to a tragic CONSEQUENCES OF ACUTE KIDNEY FAILURE after taking SULFANILAMIDE IN GLYCOL SOLUTIONS

1 Archiv fur Toxicologie 2 Copeland Bill in U.S

ANTIQUITY 1 contains information pertaining to many recognized POISONS, including HEMLOCK, ACONITE, OPIUM and METALS such as lead, copper and antimony. 2 Classify poisons into Plants, Animals, Minerals. Also created DE MATERIA MEDICA which contains references to some 600 PLANTS 3 drunk regularly a mixture of compaction (includes 36 INGREDIENTS) to protect him from assassination.

. 1 Ebers papyrus (1500 BC) 2 Dioscorides 3 King Mithridates VI of Pontus

1 First journal of experimental toxicology "__" in 1930 2 response to a tragic CONSEQUENCES OF ACUTE KIDNEY FAILURE after taking SULFANILAMIDE IN GLYCOL SOLUTIONS

1 Archiv fur Toxicologie 2 Copeland Bill in U.S

ANTIQUITY 1 The arrows of the Almighty are in me, my spirit drinks in their poison; God's terrors are marshaled against me.

1 Book of Job (circa 1400 B.C)

1 First journal of experimental toxicology "__" in 1930 2 response to a tragic CONSEQUENCES OF ACUTE KIDNEY FAILURE after taking SULFANILAMIDE IN GLYCOL SOLUTIONS

1 Archiv fur Toxicologie 2 Copeland Bill in U.S

MIDDLE AGES 1 DISSERTATION of treatment of poisoning of INSECTS, SNAKES, and Mad dogs Famous writings: TREATISE ON POISONS AND THEIR ANTIDOTES 2 Talks about the ONSET OF ACTION, POTENCY SITE OF ACTION, CLINICAL SIGNS & SYMPTOMS Tested toxic concoction

. 1 Maimonides (A.D 1135- 1204) 2 Catherine de Medici or Catherine de Mecici

1 First journal of experimental toxicology "__" in 1930 2 response to a tragic CONSEQUENCES OF ACUTE KIDNEY FAILURE after taking SULFANILAMIDE IN GLYCOL SOLUTIONS

1 Archiv fur Toxicologie 2 Copeland Bill in U.S

(Describe the subject of bioavailability, noting that MILK, BUTTER and CREAM could DELAY INTESTINAL ABSORPTION. )

TREATISE ON POISONS AND THEIR ANTIDOTES by Maimonides (A.D 1135-1204)

1 First journal of experimental toxicology "__" in 1930 2 response to a tragic CONSEQUENCES OF ACUTE KIDNEY FAILURE after taking SULFANILAMIDE IN GLYCOL SOLUTIONS

1 Archiv fur Toxicologie 2 Copeland Bill in U.S

RENAISSANCE 1 Focused on timely toxic agents as chemical entity "All substances are poisons; there is none that is not a poison. The right dose differentiates a poison from a remedy" 2 Identified that SOOT is the reason for Scrotal Cancer development in Chimney cleaners. First report of POLYAROMATIC HYDROCARBON CARCINOGENECITY

. 1 Paracelsus (1493-1541) 2 Percival Pott (1775)

1 First journal of experimental toxicology "__" in 1930 2 response to a tragic CONSEQUENCES OF ACUTE KIDNEY FAILURE after taking SULFANILAMIDE IN GLYCOL SOLUTIONS

1 Archiv fur Toxicologie 2 Copeland Bill in U.S

Book by Paracelsus which IDENTIFY THE TOXICITY OF THE MERCURY and LEAD from GOLDSMITHING and AGRICOLA. Also the ETIOLOGY OF MINER’S DISEASE along with the treatment and prevention strategies.

On the Miner's Sickness and Other Diseases of Miners

1 First journal of experimental toxicology "__" in 1930 2 response to a tragic CONSEQUENCES OF ACUTE KIDNEY FAILURE after taking SULFANILAMIDE IN GLYCOL SOLUTIONS

1 Archiv fur Toxicologie 2 Copeland Bill in U.S

CARBONACEOUS SUBSTANCE produced during incomplete combustion of coal.

Soot

Cleaners of chimney sweep later on developed this kind of cancer and he reported that when there is repeated exposure or inhaled on the soot particularly in male

Scrotal cancer

Experimental toxicology accompanied the growth of organic chemistry

Age of Enlightenment- 19th century

Age of Enlightenment- 19th century 1 Starts the FORENSIC TOXICOLOGY – he used autopsy material and chemical analysis systemically as a Legal proof of poisoning 2 studied the MECHANISM OF ACTION EMETINE and STRYCHNINE

. 1 Orfila (1787-1853) 2 Magendie (1783-1885)

1 The discovered emetine is both __ 2 Causes DAMAGE IN SKELETAL MUSCLE and also in the cardiac tissue 3 DAMAGES THE HEART 4 (highly toxic crystalline alkaloid) It is colorless and bitter tasting and usually used as pesticides.

1 myotoxic & cardiotoxic 2 MYOTOXIC 3 CARDIOTOXIC 4 Strychnine

Age of Enlightenment- 19th century 1 Published much of the early work on the TOXICITY OF NARCOTICS, METHANOL, GLYCEROL, ACROLEIN, & CHLOROFORM. Trained many students who later become toxicologist and pharmacologist around the globe

. 1 Oswald Schmiedeberg (1838 1921)

§ Started in late 1950s § Toxicology is definitely understood especially the mechanism § The prevalent use of patent medicines led to several incidents of poisonings from these predicaments.

Modern Toxicology

In this timeframe the discovery of radioactivity and vitamins, • Use of large bioassays, harmful to laboratory animals

1890s and early 1900s

1 First journal of experimental toxicology "__" in 1930 2 response to a tragic CONSEQUENCES OF ACUTE KIDNEY FAILURE after taking SULFANILAMIDE IN GLYCOL SOLUTIONS

1 Archiv fur Toxicologie 2 Copeland Bill in U.S

Identifies the cellular, biochemical, and molecular mechanisms by which chemicals exert toxic effects on living organisms Useful in the design and production of safer chemicals and in rational therapy for chemical poisoning and treatment of disease.

Mechanistic Toxicology

Concerned directly with toxicity testing Provide information for safety evaluation and also regulatory requirement o They are like part of the FDA

Descriptive toxicology

Involved in the establishment of standards or the amount of chemicals permitted in foods, drugs, ambient air, industrial atmospheres, and drinking water DIRECTLY INVOLVED WITH THE FDA Responsibility for deciding on the basis of data provided by descriptive and mechanistic toxicologist

Regulatory toxicology

Primarily focused on the medico legal on the harmful effects of chemical in humans and animals Therefore they are the one who conduct autopsy on the poison victims Hybrid of analytic chemistry and fundamental toxicologic principles

Forensic Toxicology

Concerned with disease cause by uniquely associated by toxic substance. They focused more on identifying the disease such as manifestation of signs and symptoms for a particular toxic substance

Clinical toxicology

Focused on the impact of different chemical pollutants on the environment especially in biological organisms

Environmental toxicology

The study of adverse effects on the developing organism that may result from exposure to chemical or physical agents before conception (either parent), during prenatal development, or postnatally until the time of puberty

Developmental toxicology

The study of the occurrence of adverse effects on the male or female reproductive system that may result from exposure to chemical or physical agents Study of occurrence of adverse effects for the male and female Focus on the agents of sterility Scrotal cancer caused by the soote

Reproductive toxicology

Classification of Toxic Agents

1 Toxin 2 Toxicant

O refers to toxic substances that are PRODUCED BY BIOLOGICAL SYSTEMS such as plants, animals, fungi, or bacteria o May be CLASSIFIED OF THEIR PHYSICAL STATE, CHEMICAL STABILITY OR REACTIVITY, GENERAL CHEMICAL STRUCTURE, OR POISONING POTENTIAL

TOXIN

O toxic substances that are produced by or are a BY-PRODUCT OF HUMAN ACTIVITIES o Toxic substances that are SYNTHETICALLY PRODUCED BY HUMAN ACTIVITY (pesticides, insecticides)

TOXICANT

1 Expected side effect in the pharmaceutical drug. It is always associated with therapeutic effects 2 not common, Unexpected, undesirable effect. Not all patient is automatic can feel adverse effect

1 Side effect 2 Adverse effect

Immunologically mediated adverse reaction to a chemical resulting from PREVIOUS SENSITIZATION to that chemical or to a structurally similar to a chemical that you are exposed to DOSE RELATED Repeated exposure that is structurally similar with the chemical that you are exposed to

Allergic Reactions hypersensitivity, allergic reaction, sensitization reaction

1 o genetically determined abnormal reactivity to a chemical o NON DOSE RELATED 2 The response observed is usually qualitatively similar to that observed in all individuals.

1 Idiosyncratic Reactions 2 Chemical idiosyncrasy

1 o Occurs very rapidly or after single administration or exposure to particular substance o Example : STING BY BEE 2 o Delayed toxic effects usually they occur after the lapse of sometime meaning in year before to develop or within months

1 Immediate toxicity 2 Delayed toxicity

1 The only organ that regenerates 2 an injury from here is largely IRREVERSIBLE because its cells are differentiated and cannot be replaced. 3 __ effects of chemicals, once they occur, are usually considered irreversible toxic effects

1 Liver 2 CNS injury 3 Carcinogenic and teratogenic

1 OCCUR AT THE SITE OF FIRST CONTACT between the BIOLOGICAL SYSTEM and the TOXICANT. WITHIN A PARTICULAR SITE or mostly in SKIN AREA EXERT TOXICITY 2 REQUIRES ABSORPTION and DISTRIBUTION of a TOXICANT from its ENTRY POINT to a DISTANT SITE, at which DELETERIOUS EFFECTS ARE PRODUCED. It AFFECTS DIFFERENT ORGANS

1 Local Toxicity 2 Systemic toxicity

1 Target organs in order of frequency of involvement in systemic toxicity are: 2 __ are seldom target tissues or systemic effects.

1) 1 CNS 2 circulatory system; 3 the blood and hematopoietic system; 4 visceral organs such as the liver, kidney, and lung; and the 5 skin 2) muscles and bones

Interaction of chemicals

1 Additive effect 2 Synergistic effect 3 Potentiation 4 Antagonism

Interaction of chemicals 1) most commonly observed when two chemicals are given together occurs when the COMBINED EFFECT OF TWO CHEMICALS IS EQUAL TO THE SUM THE EFFECTS OF EACH AGENT GIVEN ALONE 1+1= 2 2) occurs when the combined effects of two chemicals are MUCH GREATER THAN THE SUM OF THE EFFECTS of each agent given alone 1+1=3 PRODUCES MUCH GREATER EFFECTS

1 Additive effect 2 Synergistic effect

Interaction of chemicals 1 one substance does NOT HAVE A TOXIC EFFECT on a certain organ or system but WHEN ADDED TO ANOTHER CHEMICAL MAKES THAT CHEMICAL MUCH MORE TOXIC 2 § when TWO CHEMICALS administered together INTERFERE WITH EACH OTHER’S ACTIONS or one interferes with the action of the other MOA of Antidotes

. 1 Potentiation 2 Antagonism

4 TYPES OF ANTAGONISM

1 Functional Antagonism 2 Chemical Antagonism / Inactivation 3 Dispositional Antagonism 4 Receptor Antagonism

O Occurs when TWO CHEMICALS COUNTERBALANCE EACH OTHER by PRODUCING OPPOSITE EFFECTS on the same physiologic function. o For example, the marked all in blood pressure during severe barbiturate intoxication can be effectively antagonized by the intravenous administration of a vasopressor agent such as norepinephrine or metaraminol.

Functional Antagonism

O simply a CHEMICAL REACTION BETWEEN TWO COMPOUNDS that PRODUCES a LESS TOXIC PRODUCT o For example, chelators o metal ions decrease metal toxicity and antitoxins antagonize the action of various animal toxins

Chemical Antagonism / Inactivation

O OCCURS WHEN the ABSORPTION BIOTRANSFORMATION, DISTRIBUTION, or EXCRETION of a CHEMICAL is ALTERED so that the CONCENTRATION and/or duration of the CHEMICAL at the target organ are DIMINISHED o depend on how fast the victim or one person to do this ADME o For example madaming laman ang tiyan then matagal ang absorption ng poison

Dispositional Antagonism

O occurs when TWO CHEMICALS THAT BIND TO THE SAME RECEPTOR produce LESS OF AN EFFECT WHEN GIVEN TOGETHER than the ADDITION OF THEIR SEPARATE EFFECTS or when one chemical antagonizes the effect of the second chemical o Receptor antagonists are often termed blockers. o For example; ANTIHISTAMINE it will bind to histidine decarboxylase o Binding of enzyme and active site

Receptor Antagonism

§ A STATE OF DECREASED RESPONSIVENESS to a TOXIC EFFECT OF A CHEMICAL resulting from prior exposure to that chemical or a structurally related chemical

Tolerance

Two major mechanisms are RESPONSIBLE FOR TOLERANCE:

1 due to a DECREASED AMOUNT OF TOXICANT REACHING THE SITE where the TOXIC EFFECT IS PRODUCED (dispositional tolerance) 2 due to a REDUCED RESPONSIVENESS of a TISSUE to the CHEMICAL

CHARACTERISTICS OF EXPOSURE The major routes (pathways) by which toxic agents gain access to the body are:

1 gastrointestinal tract (ingestion), 2 lungs(inhalation), 3 skin (topical, percutaneous, or dermal), 4 parenteral (other than intestinal canal) routes.

CHARACTERISTICS OF EXPOSURE Descending order of effectiveness/can give toxic effects:

1) IV, 2 Inhalational, 3 Intraperitoneal, 4 Subcutaneous, 5 Intramuscular, 6 intradermal, 7 oral and 8 dermal unless broken

DURATION AND FREQUENCY OF EXPOSURE 1) defined as EXPOSURE TO A CHEMICAL OR LESS THAN 24 HR. 2) refers to CONTINUOUS EXPOSURE OR LESS THAN 24 H, MOST FREQUENTLY 4 H. 3) Repeated exposure for 1 month or less 4) 1-3 months (REPEATED EXPOSURE FOR SEVERAL WEEKS OR MONTHS) 5) 3 months- years and above.

. 1 Acute 2 Acute exposure by inhalation 3 Subacute 4 Subchronic 5 Chronic

Repeated exposure is divided into three categories:

1 subacute, 2 subchronic, and 3 chronic.

Correlative relationship of the characteristic response of EXPOSURE and SPECTRUM OF EFFECTS of toxic agents Mostly CONSISTENT WITH THE DOSE OR AMOUNT OF TOXICANT INCREASES THE DOSE,= INCREASE THE RESPONSE or TOXIC EFFECT of one individual but sometime different response also will manifest to a population

Dose-Response Relationship

Dose-Response Two Types

1 Individual, or Graded Dose-Response Relationship 2 Quantal Dose-Response Relationship-Normal or Gaussian Distribution

§ characterized by a DOSE-RELATED INCREASE IN THE SEVERITY OF THE RESPONSE § As you INCREASE THE DOSE of the ORGANOPHOSPHATE the PERCENT INHIBITION also INCREASE. Therefore in this response there is DIRECTLY PROPORTIONAL relationship between the RESPONSE OF INHIBITION AND THE DOSE

Individual, or Graded Dose-Response Relationship

§ Population is classified as either a “responder” or a “nonresponder.” § LD50 - means you are trying to look on the 50% died on animal tested by giving a single dose of the substance then it is expected to death in 50% of the animal tested

Quantal Dose-Response Relationship-Normal or Gaussian Distribution

1 __ means ALL OR NONE 2 means you are trying to look on the 50% died on animal tested by giving a single dose of the substance then it is expected to death in 50% of the animal tested

1 QUANTAL 2 LD50

1 animals that RESPOND AT LOWER DOSE 2 Animals that DIED AT HIGHER DOSE

1 HYPERSUSCEPTIBLE 2 RESISTANT

2. Quantal Dose-Response Relationships: sigmoid dose-response curve 1) +-1 SD = __ population (%) 2) +-2 SD = __ population (%) 3) +-3 SD = __ population (%)

. 1) 68.3% 2) 96.5% 3) 99.7%

Non-nutritional toxic substances • U-shaped curve • May also impart beneficial or stimulatory effects at low doses but, at higher doses, they produce adverse effects. • EXAMPLE: For example, chronic alcohol consumption is well recognized to increase the risk of esophageal cancer, liver cancer, and cirrhosis of the liver at relatively high doses, and this response is dose related

Hormesis

RATIO of the DOSE REQUIRED TO PRODUCE TOXIC EFFECT and dose needed to ELICIT THE DESIRED THERAPEUTIC RESPONSE

Therapeutic Index = : TD50/ED50

1 The LARGER the ratio between the TD50 and ED50, the __ the RELATIVE SAFETY of the drug or tested substance

Greater larger ratio td50 & ed50 = MORE SAFE

§ INDICATOR OF THE MAGNITUDE OF THE DIFFERENCE BETWEEN AS ESTIMATED EXPOSE DOSE TO A HUMAN POPULATION and the no observable adverse effect level that is determined in the experimental animals § BETWEEN 1% and 99% RESPONDER

Margins of safety = LD1/ED99

1 range of doses over which a chemical produces increasing response 2 - reflects the limit of the dose response relationship on the response axis to a certain chemical o Increasing the dose will increase the response however, D has the maximal efficacy

1 POTENCY 2 EFFICACY

Variations in Toxic Responses:

1 Selective Toxicity 2 Species Differences 3 Individual Differences in response

Means that a CHEMICAL PRODUCES INJURY TO ONE KIND OF LIVING MATTER WITHOUT HARMING ANOTHER FORM OF LIFE eventhough the two may exist in intimate contact o For example BAYGON only insects are harmem

Selective Toxicity

O Experimental RESULT MAY DIFFER IN DIFFERENT SPECIES o Between man and animal Identifying the mechanistic basis or species di differences in response to chemicals establishes the relevance of animal data to human response EX. For example when tested in animals it developed TUMORS but when tested in humans no TUMORS was developed

Species Differences

O Due to GENETIC DIFFERENCES THAT HAS NO SIDE EFFECTS o GENETIC POLYMORPHISM o Idiosyncratic

Individual Differences in response

1 When a toxicant is delivered intended target, it reacts with it and causes 1 __ which leads to 2 __ 2 Sometimes, the toxicant will not reach its target molecule but rather it can adversely influence the __, causing __

1) 1 cellular dysfunction 2 toxicity 2) 1 biological environment 2 molecular, organellar, cellular, or organ dysfunction leading to deleterious effects. So its much worse if a toxicant does not reach the target site

B. DISTRIBUTION TO AND AWAY FROM THE TARGET - Specialized Barriers 1 Because brain capillaries LACK __ and have extremely tight junctions, substances that are __ CANNOT ENTER THE BRAIN except by __ 2 The spermatogenic cells are surrounded by __ that are tightly joined to form the __. 3 Transfer of hydrophilic toxicants across the placenta is also restricted. However, none of these barriers are effective against lipophilic substances.

. 1) 1 fenestrae 2 hydrophilic, 3 active transport 2) 1 Sertoli cells, 2 blood–testis barrier

Mechanism of Toxicity STEPS

Step 1 - Delivery - Delivery of toxicant to its target molecule. Step 2 - Either INTERACT w/ MOLECULES or ALTER ENVIRONMENT Step 3 - Trigger perturbation in cell function/structure - changing the normal state of cell function in other molecules. Step 4 - Initiate repair - Body initiate repair mechanisms at cellular/ tissue level - If beyond repair, toxicity occurs DIAI (DIAY)

. 1) 1 fenestrae 2 hydrophilic, 3 active transport 2) 1 Sertoli cells, 2 blood–testis barrier

The CHEMICAL SPECIES that REACTS WITH THE ENDOGENOUS TARGET MOLECULE or CRITICALLY ALTERS THE BIOLOGICAL ENVIRONMENT, initiating structural and/or functional ALTERATIONS that result in toxicity. It CAN BE: - can be the ORIGINAL CHEMICAL to which the organism is exposed to (Parent Compound) - can be the a metabolite or a REACTIVE OXYGEN OR NITROGEN SPECIES (ROS or RNS) during the BIOTRANSFORMATION of the toxicant - can be ENDOGENOUS MOLECULE

Ultimate Toxicant

. 1) 1 fenestrae 2 hydrophilic, 3 active transport 2) 1 Sertoli cells, 2 blood–testis barrier

(STEP 1 --- DELIVERY: FROM THE SITE OF EXPOSURE TO THE TARGET) 1 Theoretically, the ultimate toxicant's concentration and persistence at the site of action determine __ 2 The CONCENTRATION of the ULTIMATE TOXICANT at the target molecule depends on the __

. 1 how STRONG/INTENSE a toxic effect will be. 2 relative effectiveness of the PROCESSES that INCREASE or DECREASE ITS CONCENTRATION at the target site

(STEP 1 --- DELIVERY: FROM THE SITE OF EXPOSURE TO THE TARGET) ULTIMATE TOXICANT 1 Its INCREASED CONCENTRATION is facilitated by __ 2 DECREASED CONCENTRATION is facilitated by __

. 1 - Absorption, - Distribution to the site of action, - Reabsorption, and - Toxication ADR T 2 - Presystemic elimination, - Distribution away from the site of action, - Excretion, and - Detoxication. PDED

A. ABSORPTION VS PRESYSTEMIC ELIMINATION 1 is the process by which a CHEMICAL IS TRANSFERRED FROM THE SITE OF EXPOSURE, usually an internal or external body surface, INTO the SYSTEMIC CIRCULATION. 2 Factors that influence this:

1 Absorption 2  Concentration  Surface area of exposure  Characteristics of the epithelial layer through which the toxicant is being absorbed  lipid solubility (MOST IMPORTANT)

A. ABSORPTION VS PRESYSTEMIC ELIMINATION 1 Toxicants may be eliminated as they move from the site of exposure to the systemic circulation. COMMON for CHEMICALS ABSORBED FROM THE GASTROINTESTINAL (GI) TRACT - they must first pass through the GI mucosal cells, liver, and lung before being distributed to the rest of the body by the systemic circulation. generally REDUCES THE TOXIC EFFECTS OF CHEMICALS that reach their target sites by way of the systemic circulation. - may CONTRIBUTE TO INJURY to these sites (digestive mucosa, liver, & lungs) 2 The __may eliminate a significant fraction of a toxicant during its passage through these tissues

1 PRESYSTEMIC ELIMINATION 2 GI mucosa and the liver

B. DISTRIBUTION TO AND AWAY FROM THE TARGET 1 Toxicants exit the blood during the __, travel through the extracellular space, and reach their target site, which is a __on the exterior or interior of a specific type of cell. 2 Chemicals also may be distributed to the site or sites of toxication, which is an __, where the ultimate toxicant is formed through __

. 1 distribution phase, macromolecule 2 intracellular enzyme, biotransformation

B. DISTRIBUTION TO AND AWAY FROM THE TARGET 1 Mechanisms facilitating DISTRIBUTION TO A TARGET

1) Porosity of the Capillary Endothelium 2) Specialized Transport Across the Membrane 3) Accumulation in Cell Organelles 4) Reversible Intracellular Binding PaSAR (naka PaSAR)

(Mechanisms facilitating DISTRIBUTION TO A TARGET) - Porosity of the Capillary Endothelium Endothelial cells in the hepatic sinusoids and in the renal peritubular capillaries have __ which has a diameter of __ that permit passage of even __

1 large fenestrae (opening) 2 (50 to 150 nm in diameter) 3 protein bound xenobiotics

(Mechanisms facilitating DISTRIBUTION TO A TARGET) - Specialized Transport Across the Membrane 1 __ can contribute to the delivery of toxicants to intracellular targets. 2 __ FACILITATE the ENTRY of TOXICANTS into specific cells, rendering those cells targets. 3 The __ of some TOXICANT– PROTEIN COMPLEXES occurs in some cells as well.

. 1 Specialized ion channels and Membrane transporters 2) 1 Na+ & K+ ATPase, 2 Voltagegated Ca2+ channels, 3 Carrier-mediated uptake, 4 Endocytosis, and 5 Membrane recycling 3) Endocytosis

(Mechanisms facilitating DISTRIBUTION TO A TARGET) - Accumulation in Cell Organelles 1 __ accumulate in lysosomes as well as mitochondria. 2 Lysosomal accumulation OCCURS BY __, that is, DIFFUSION OF THE AMINE in UNPROTONATED FORM into the ACIDIC INTERIOR of the organelle, where the amine is protonated, PREVENTING its EFFLUX, so that it IMPAIRS PHOSPHOLIPID DEGRADATION. 3 Mitochondrial accumulation takes place __. The AMINE is PROTONATED in the INTERMEMBRANE SPACE and then sucked into the matrix space by the STRONG NEGATIVE POTENTIAL (–220 mV), where it may IMPAIR β OXIDATION and OXIDATIVE PHOSPHORYLATION.

. 1 Amphipathic xenobiotics w/ protonatable amine group and lipophilic character 2 pH TRAPPING 3 Electrophoretically.

(Mechanisms facilitating DISTRIBUTION TO A TARGET) - Reversible Intracellular Binding 1 Chemicals that BIND to MELANIN, such as __ accumulate in cells that contain melanin

. 1 organic and inorganic cations 2 polycyclic aromatic hydrocarbons

B. DISTRIBUTION TO AND AWAY FROM THE TARGET 1 Mechanisms OPPOSING DISTRIBUTION TO A TARGET

1) Binding to Plasma Proteins 2 Specialized Barriers 3 Distribution to Storage Sites 4 Association with Intracellular Binding Proteins 5 Export from Cells

(Mechanisms OPPOSING DISTRIBUTION TO A TARGET) - Binding to Plasma Proteins Most xenobiotics must __ from proteins in order to leave the blood and enter cells. As a result, the EFFECTS & ELIMINATION of TOXICANTS are DELAYED & PROLONGED by __ to plasma proteins.

. 1 dissociate 2 strong binding

(Mechanisms OPPOSING DISTRIBUTION TO A TARGET) - Specialized Barriers 1 Because brain capillaries LACK __ and have extremely tight junctions, substances that are __ CANNOT ENTER THE BRAIN except by __ 2 The spermatogenic cells are surrounded by __ that are tightly joined to form the __. 3 Transfer of HYDROPHILIC TOXICANTS across the placenta is RESTRICTED. However, NONE of these BARRIERS are EFFECTIVE AGAINST __

. 1) 1 fenestrae 2 hydrophilic, 3 active transport 2) 1 Sertoli cells, 2 blood–testis barrier 3 lipophilic substances. Hydrophilic = Restricted Lipophilic = Not Restricted

(Mechanisms OPPOSING DISTRIBUTION TO A TARGET) - Distribution to Storage Sites 1 Some chemicals accumulate in tissues (i.e., storage sites) where they exert __ 2  Such storage __ toxicant availability for their target site

. 1 NO significant effects. 2 decreases

(Mechanisms OPPOSING DISTRIBUTION TO A TARGET) - Association with Intracellular Binding Proteins 1 Binding to NONTARGET INTRACELLULAR SITES, such as __, TEMPORARILY REDUCES the CONCENTRATION OF TOXICANTS at the target site.

. 1 metallothionein