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PK Gupta Series 9: Biotranformation –Toxicokinetics TOXICOLOGY Question and Answer bank

TOXICOLOGY Question and Answer bank is aimed to make the study of toxicology simple and understandable

Absorption 

Q. Define absorption
Absorption is defined as the process of movement of unchanged compound from its sites of administration or exposure to the blood stream.
Q.  Define distribution of xenobiotics? 
Distribution may be defined as a process by which xenobiotics move throughout the body and reach their site of action (extracellular fluid and tissues).
Explanation: Once absorbed, a toxicant typically enters the interstitial fluid at the site of absorption and then passes into the tissue cells or enters the blood and/or lymph. Blood is moved rapidly through the body by the cardiovascular circulatory system and this process constitutes the major mechanism whereby absorbed chemicals are distributed to the various organs and tissues of the body. The entrance of xenobiotics to some tissues is restricted by special barriers (e.g., blood–brain barrier, blood–testes barrier and blood–placenta barrier) that form continuous cellular layers with tight junctions that prevent movement of toxicants into tissues by passive diffusion through intercellular spaces. To gain entry into these protected tissues, toxicants must pass through lipid cell membranes, either by penetrating the lipid membranes directly, or by active or facilitated transport through trans-membrane transporter proteins.
Q. Define excretion of xenobiotics.
Excretion may be defined as a process by which toxicants and/or their metabolites are irreversibly transferred from body to external environment. Thus excretion is one of the primary mechanisms of protecting the body from the toxic effects of toxicants through the elimination of these compounds from the body. Compounds that are rapidly eliminated are less likely to accumulate in tissues and damage critical cells. Although the terms elimination and excretion are sometimes used synonymously, the former term encompasses all the processes that decrease the amount of parent compound in the body, including biotransformation.
Q. Define ADME?
ADME is an abbreviation in pharmacokinetics and pharmacology for "absorption, distribution, metabolism, and excretion," and describes the disposition of a pharmaceutical compound within an organism.
Q.  What are the primary routes of exposure for toxic substances?
Following are the routes of exposure
a) oral
b) respiratory
c) dermal.
d) parentral
Explanation: Oral or gastrointestinal (GI), respiratory, and dermal systems are lined with epithelia that present significant barriers to the entry of foreign substances due to tight junctions between their cells, or continuous lipid layers in the case of skin.. The onset, duration and intensity of a substance’s toxic effects are therefore dependent on the toxicant’s ability to permeate lipid cell membranes directly, and its interactions with transporter proteins. Dermal penetration is unique in the sense that the outer epithelial cellular layers (corneocytes) are non-viable and do not contain transporter proteins. Absorption, in this case, is therefore dependent on the ability of toxicants to penetrate the intercellular lipid matrix found between corneocytes.
The plasma membranes surrounding all these cells are remarkably similar (such as the stratified epithelium of the skin, the thin cell layers of the lungs or the GI tract, capillary endothelium, and ultimately the cells of the target organ The plasma membranes surrounding all these cells are remarkably similar.
Q. What is plasma membrane?
The biological cell has a fundamental structure, the cell membrane or, as it is often called, the plasma membrane. The thickness of the membranes is of the order of 100Å.
Explanation: The majority of chemicals to which most of the population is exposed are organic acids or bases. An acid with a low pKa is a strong acid and one with a high pKa is a weak acid. Conversely, a base with a low pKa is a weak base and one with a high pKa is a strong base. The weak acids are absorbed readily from the stomach because they all are almost completely non ionized at the gastric pH. Weak bases are not absorbed well; indeed, they would tend to accumulate within the stomach at the expense of the chemical agent in the blood stream. Naturally, in the more alkaline intestine, bases would be absorbed better, acids more poorly.
     The concentration of a chemical that is in ionized or in non-ionized form depends on both pKa of the chemical and the pH of the solution in which it is dissolved. The relationship may be derived by mathematical transformation of Henderson Hasselbalch equation:
     It is therefore assumed that the gastric mucosal wall acts as a simple lipoid barrier which is permeable only to the lipid-soluble, non-dissociated form of the acid. Thus, in plasma, the ratio of non-ionized to ionized drug is 1:1000; in gastric juice, the ratio is 1:0.001. The total concentration ratio between the plasma and the gastric sides of the barrier is therefore 1000:1. For a weak base with a pKa of 4.4, the ratio is reversed.

 Distribution

Q.     Describe factors that determine a compound’s rate and extent of distribution.
Factors that influence distribution include:
      (a)      Molecular size i.e. physicochemical properties of compound
     (b)      Lipophilicity
      (c)      Plasma protein and tissue binding
     (d)      Blood flow and organ size
      (e)      Special compartmental and barriers e.g. blood-brain barrier; blood-cerebrospinal barrier; placental barrier and other barriers
      (f)      Availability of special transport system
     (g)      The ability to interact with trans-membrane transporter proteins , and
     (h)      Disease state, etc.
Explanation: After absorption into the blood stream, the chemicals penetrate in the various fluid compartments- (i) plasma, (ii) interstitial fluid, (iii) transcellular fluid, and (iv) cellular fluids. The non-ionized lipid/soluble fractions penetrate most readily. Some chemicals may accumulate in various areas as a result of binding or due to their affinity for fat.
Q. Describe important blood organ barriers for transport of xenobiotics.
For transport of xenobiotics, the effective tight junction occurs at the level of capillary endothelium e.g., brain, placenta and thymus barriers. These barriers are called blood-organ barriers. In blood-bile barriers, the blood has direct access to the membranes of the hepatocytes. Tight junctions formed by adjacent hepatocytes constitute the physical barrier immediately interposed between blood and bile. Some of the so called blood-organ barriers do not directly involve the blood. For example, in blood-urine barrier tight junction occurs near the luminal surface of bladder epithelial cells and in the blood testes barriers within the seminiferous tubules. Thus blood-testes barrier resembles the blood-urine barriers more than the blood-brain barriers with which it is often compared. A few important barriers are:            
a)      Blood-Brain Barrier
b)      Placental Barrier
c)       Blood-Testes Barrier
Q. Describe in brief different factors that affect distribution and tissue retention of drugs
The following factors affect the distribution and retention of drugs:
a)       blood flow
b)       volume of distribution
c)        enzyme induction
d)      chemical interaction
e)       age and sex differences
f)       genetic factors
g)      binding with proteins
h)      storage in various body tissues including brain and fat
Q.  Discuss briefly routes of excretion of xenobiotics? 
The principal organs of excretion, is called renal excretion, excretion by organs other than kidneys is known as extra-renal or non renal excretion.
The biliary route of excretion plays a major role in the elimination of anions, cations, and non-ionized molecules containing both polar and lipophilic groups. The biliary excretion of foreign compounds varies with species and is generally highest in the dog and rat. The hepatic excretory system is not fully developed in the infants and is additional reason for some compounds being more toxic in infants than in the adults. More information is required to see if increased toxicity of some compounds in the infants is due to this reason.
In addition to renal excretion, there are non renal or extra renal excretion through GI tract, expired air, sweat, saliva, milk, vaginal secretions and other route such as lachrymal fluid, intestinal fluid, tracheobronchial secretions, etc.

Biotransformation

Q. What is disposition of a chemical?   
The disposition of a chemical or xenobiotic is defined as the composite actions of its absorption, distribution, biotransformation, and elimination.
Explanation
To reach the target site, the toxicant must be absorbed effectively into blood stream, distributed efficiently to site of action, and subsequently metabolized and excreted from the body.  The processes of absorption and distribution are responsible for placement or deployment of these toxicants in the body, and metabolism and excretion, for elimination of the toxicant from the body. All these processes involve passage across biological membranes.
Q. What are the functions of biotransformation. Give suitable examples
Biotransformation performs the following functions
      (a)      It causes conversion of an active compound to less active called inactivation or detoxification. Examples are phenobarbitone to p-hydroxyphenobarbitone; DDT to metabolite products DDE and DDA
     (b)      It causes conversion of an active compound to more active metabolite(s) called bioactivation. Examples are malathion to malaoxon or parathion to paraoxon and acetonitrile to cyanide
      (c)      It causes conversion of an inactive compound (i.e. pro-drug or precursor compound) to active metabolite(s) called activation. Examples are phenacetin to paracetamol, thiocyanates to cyanide
     (d)      It causes conversion of an active compound to equally active metabolite(s) (no change in the activity). Examples are dichrotophos to monochrotophos, digitoxin to digoxin
      (e)      It causes conversion of an active compound to active metabolite(s) having entirely pharmacological/toxicological activity (change in activity). Examples are Iproniazid (antidepressant) to isoniazid (antitubercular), Alflatoxin B1 (hepatotoxin) to aflatoxin M1 (carcinogen).

Metabolizing enzymes

Q. What are xenobiotic metabolizing enzymes?
These enzymes can be divided into two main groups:
               (a)      Microsomal enzymes
               (b)      Non-microsomal enzymes
Microsomal enzymes: These enzymes are present in the endoplasmic reticulum (ER) (especially smooth) of liver and other tissues.
Non-microsomal enzymes: Enzymes occurring in organelles/sites other than microsomes are called non-microsomal enzymes. These are usually present in the cytoplasm, plasma, and mitochondria.
Q. Describe briefly fine pathways of biotransformation
The major transformation reactions for xenobiotics are divided into two phases known as Phase I and Phase II.
a)       Phase I Reactions (Non-synthetic or Non-conjugative Phase)
Phase I reactions modify the compound’s structure by adding a functional group. This allows the substance to interact with a reactive group, such as –OH, SH, -NHor –COOH. Most of these reactions involve different types of microsomal enzymes, except a few where reactions involve non-microsomal enzymes. Phase I reactions usually yield products with decreased activity. However, some may give rise to products with similar or even greater activity.
Oxidation: It is the most common reaction and may take place in a number of ways such as hydroxylation, deamination, desulfurization, dealkylation or sulfoxide formation, etc.
In the biotransformation of lipophilic xenobiotics, microsomal oxidation is the most prominent reaction where microsomal enzymes associated with smooth endoplasmic reticulum of hepatocytes are involved and the enzyme cytrochrome P-450, a heme-protein, which is a part of an enzyme system termed as mixed function oxidase (MFO) system, plays an important role.
The other enzyme systems of Phase I biotransformation are involved in metabolism when the appropriate functional groups are available e.g. alcohol dehydrogenase is involved in the biotransformation of alcohols and aldehydes, monomine oxidase is a flavine adenine dinucleotide (FAD)-containing enzyme that catalyses the oxidative deamination. Epoxide hydrolases are enzymes that add water across epoxide bonds to form diols. A number of carbroxyl esterases are responsible for biotransformation of certain compounds including organophosphates. The extent to which these metabolic reactions take place appear to vary with the species.
Reduction: Reduction is acceptance of one or more electrons(s) or their equivalent from another substrate. Biotransformation by reduction is also capable of generating polar functional groups such as hydroxyl and amino groups which can undergo further biotransformation or conjugation. Many reductive reactions are exact opposite of oxidative reactions.
Hydrolysis: It is the process of cleaving of a foreign compound by the addition of water. It occurs both in the cytoplasm and smooth endoplasmic reticulum. It is an important metabolic pathway for compounds with an ester linkage (-CO, O-) or an amide (-CO, HN-) bond. The cleavage of esters or amides generates nucleophilic compounds which undergo conjugation.
b)                  Phase II Reactions or Conjugation/Synthetic Reactions 
Phase II reactions (conjugation/synthetic reactions) includes reactions that catalyses conjugation of xenobiotics or their Phase I metabolites with endogenous substances with a water soluble molecule. In Phase II, most of the reactions involve non-microsomal process (except a few that involve microsomal enzyme). Due to biotransformation, the water solubility of a compound is typically increased.
     Synthetic reactions may take place when a xenobiotic or with a polar metabolite of phase I metabolism containing –OH, -COOH, -NH2 or –SH group that undergoes further transformation to generate non-toxic products of high polarity which are highly water soluble and readily excretable by combining with some hydrophilic endogenous moieties  Conjugating agents are glucuronic acid, acetyl, sulphate, glycine, cysteine, methionine and glutathione which conjugate with different functional groups of xenobiotics.
     Most of the phase-II biotransforming enzymes are located in the cytosol with the exception of uridine diphosphate glucuronyl transferase (UDPGT) which is a microsomal enzyme.
Q. What do you understand by induction or Inhibition of metabolizing enzymes?
a)         Induction of Enzymes
Several drugs and chemicals have ability to increase the metabolizing activity of enzymes called enzyme induction.     Microsomal enzyme induction by drugs and chemicals usually require repetitive administration of the inducing agent over a period of several days and the induction, once started, may continue for several days. Metabolizing enzyme induction has great clinical importance because it affects the plasma half-life and duration of action of xenobiotics.  
c)       Inhibition of Enzymes
Contrary to metabolizing enzyme induction, several drugs and chemicals have ability to decrease the metabolizing activity of certain enzymes called enzyme inhibition. Enzyme inhibition can be either non-specific of chromosomal enzymes, or specific of some non-microsomal enzymes (e.g. monoamine oxidase, cholinesterase and aldehyde dehydrogenase). The inhibition of hepatic microsomal enzymes mainly occurs due to administration of hepatotoxic agents, which cause either rise in the rate of enzyme degradation (e.g. carbon tetrachloride and carbon disulphide) or fall in the rate of enzyme synthesis (e.g. puromycin and dactinomycin). Enzyme inhibition may also produce undesirable xenobiotic interactions. 

 Bioactivation

Q. Describe briefly bioactivation 
Formation of harmful or highly reactive metabolic from relatively inert/non toxic chemical compounds is called bioactivation or toxication. The bioactive metabolites often interact with the body tissues to precipitate one or more forms of toxicities such as carcinogenesis, teratogenesis, tissue necrosis, etc.
     The bioactivation reactions are generally catalyzed by cytochrome P-450-dependent monooygenase systems, but some other enzymes like those in intestinal flora are also involved in some cases. The reactive metabolites primarily belong to three main categories-electrophiles, free radicals and nucleophiles. The formation of electrophiles and free radicals from relatively harmless substances/xenobiotics account for most toxicities.

Electrophiles

Q. Define electrophiles
Electrophiles are molecules which are deficient in electrons pair with a positive charge that allows them to react by sharing electron pairs with electron-rich atoms in nucleophiles. Important electrophiles are epoxides, hydroxyamines, nitroso and azoxy derivatives, nitrenium ions and elemental sulfur. These eletrophiles form covalent binding to nucleophilic tissue components such as macromolecules (proteins, nucleic acids and lipids) or low molecular weight cellular constituents to precipitate toxicity. Covalent binding to DNA is responsible for carcinogenicity and tumor formation.
Q. Define free radicals
Free radicals are molecules which contain one or more unpaired electrons (odd number of electrons) in their outer orbit.
Q. Define nucleophiles
Nucleophiles are molecules with electron-rich atoms. Formation of nucleophiles is a relatively uncommon mechanism for toxicants. Examples of toxicity induced through nucleophiles include formation of cyanides from amygdalin, acrylonitrile and sodium nitroprusside and generation of carbon monoxide from dihalomethane.

Toxicokinetics

Q. What is toxicokinetics?
Toxicokinetics (often abbreviated as 'TK') is the description of what rate a chemical will enter the body and what happens to it once it is in the body.
Q.  What do you mean by extravascular administration (EV)?
Drug or toxicant administration by any other route than the intravenous route is called EV administration.
Q. Define minimum effective concentration (MEC)
Minimum effective concentration (MEC) is the minimum concentration of drug in plasma required to produce the desirable pharmacological/therapeutic response. In case of antimicrobials, the term minimum inhibitory concentration (MIC) is used, which may be defined as the minimum concentration of antimicrobial agent in plasma required to inhibit the growth of microrganims.
Q. Define maximum safe concentration (MSC) or minimum toxic concentration (MTC)
Maximum safe concentration (MSC) or minimum toxic concentration (MTC) is the concentration of drug in plasma above which toxic effects are produced. Concentration of drug above MSC is said to be in toxic level. The drug concentration between MEC and MSC represents the therapeutic range.
Q. Define maximum plasma concentration/Peak plasma concentration (Cmax or Cpmax).
Maximum plasma concentration/Peak plasma concentration is the point of maximum concentration of drug in plasma. The maximum plasma concentration depends on administered dose and rates of absorption (absorption rate constant, Ka) and elimination (elimination rate constant, β). The peak represents the point of time when absorption equals elimination rate of the drug. It is often expressed as g/ml.
Q.  Define area under curve (AUC).
Area under curve (AUC) is the total integrated area under the plasma drug concentration-time curve. It expresses the total amount of drug that come into systemic circulation after administration of the drug
Q.  Define peak effect
Peak effect is the maximal or peak pharmacological or toxic effect produced by the drug. It is generally observed at peak plasma concentration.
Q. Define time of maximum concentration/Time of peak concentration (tmax):
Time of maximum concentration/ time of peak concentration is the time required for a drug to reach peak concentration in plasma. The faster is the absorption rate, the lower is the tmax. It is also useful in assessing efficacy of drugs used to treat acute conditions (e.g., pain) can be treated by a single dose. It is expressed in hours.
Q. Define onset of action
Onset of action: It is the beginning of pharmacological or toxicological effect or  response produced by the drug. It occurs when the plasma drug concentration just exceeds the MEC.
Q.  Define onset time
 Onset time is the time required for the drug to start producing pharmacological or toxic response. It usually corresponds to the time for the plasma concentration to reach MEC after administration of the drug.
Q.  Define duration of action
Duration of action is the time period for which pharmacological or toxic response is produced by the drug. It usually corresponds to the duration for which the plasma concentration of drug remains above the MEC level.
Q. What is zero order process or kinetic? 
Zero-order process/zero-order kinetics or constant-rate kinetics is defined as a toxicokinetic process whose rate is independent of the concentration of the xenobiotic/chemical i.e., the rate of toxicokinetic process remains constant and cannot be increased further by increasing their concentration of xenobiotic.

Q. What is first order process or kinetic? 
First-order process (first-order kinetics or linear kinetics) is defined as a toxicokinetic process whose rate is directly proportionate to the concentration of the xenobiotic/chemical i.e., greater the concentration, faster is the process.
Q.  What is mixed process or mixed order kinetic? 
Mixed- process (mixed- order kinetics, non-linear kinetic or dose-dependent kinetics) is defined as a toxicokinetic process whose rate is a mixture of both zero order and first-order processes. The mixed order process follows zero-order kinetics at high concentration and the first order kinetics at lower concentration of the xenobiotic. This type of kinetics is usually observed at increased or multiple doses of some chemicals.

Toxicokinetic models

Q.  Name three toxicokinetic models that are commonly used
i) classic toxicokinetics (traditional)
ii) non compartment models/non compartment analysis and
iii) physiological models
Q.  What are classic toxicokinetic models?
Classic toxicokinetic modeling (traditional) is simplest mean of gathering information on absorption, distribution, metabolism, and elimination of a compound and to examine the time course of blood or plasma toxicant concentration over time. In this approach the body represents as a system of one or two compartments (sometimes more than two compartments) even though the compartments do not have exact correspondence to anatomical structures or physiologic processes.
Q. What are the advantages of classic models?
             (a)        they do not require information on tissue physiology or anatomic structure;
            (b)        they are useful in predicting the toxicant concentrations in blood at different doses;
             (c)        they are useful in establishing the time course of accumulation of the toxicant,  either in its parent form or as biotransformed products during continuous or episodic exposures, in defining concentration–response (vs. dose–response) relationships and,
            (d)        provide help/guidance in the choice of effective dose and design of dosing regimen in animal toxicity studies.
Q. Define One-Compartment Open Model 
One-compartment open model is the simplest model, which considers the whole body as a single, kinetically homogeneous unit, in this model, the final distribution equilibrium between the chemical in plasma and other body fluids is attained rapidly and maintained at all times.
Q.  Define two-compartment open model
Two-compartment Open Model assumes that body is composed of two compartments-the centra l compartment and peripheral compartment. The central compartment (compartment 1) consists of blood and highly perfused organs like liver and, kidney, lungs, heart, brain , etc; the less perfused tissues (compartment 2) like skin, muscles, bone, cartilage, etc. make the peripheral compartment.
Q.  Describe the shape of time curve in two compartment model
In two-compartment open model, after intravenous (IV) bolus or extravascular administration of a single dose of toxicant the curve is biexponential. As shown in figure below linear terminal portion is elimination phase β.
Q. Describe three-compartment open model
The toxicokinetic behavior of some chemicals, which have a high affinity for a particular tissue and are under redistribution, is best interpreted according to a three compartment open model. Body is conceived as consisting of three compartments – one central and two peripheral compartments. The central compartment (compartment 1) comprises of plasma and highly perfused organs, whereas peripheral compartments 2 comprises of moderately (e.g., skin and muscles) and compartment 3 poorly perfused tissues (e.g., bone, teeth, ligaments, hair, and fat). If any chemical is administered by IV, it is first distributed immediately into the highly perfused tissues (compartment 1), then slowly into the moderately perfused tissues (compartment 2) and thereafter very slowly to the poorly perfused tissues (compartment 3). If plasma level-time profile is plotted on semi-logarithmic graph, it gives triexponential appearance.
Q. Define the term half-life
Half-life (T½) may be defined as the time taken for the concentration of a compound/ toxicant in plasma to decline by ½ or 50% of its initial value (or it may be defined as the time required for the body to eliminate half of the chemical). This value is determined during the elimination phase of a chemical; therefore, it is called as elimination half-life.
Q. What is bioavailability?
After oral or EV routes, often only a fraction of the total dose to which an animal or human is exposed gets absorbed systemically. This fraction is referred to as the bioavailability (F). Bioavailability is determined by measuring the area under plasma drug concentration versus time curve (AUC) after oral or EV routes. This is compared with AUC measured after IV bolus administration of the same drug.
     Bioavailability is a useful parameter, which is used to predict the drug efficacy after different routes of administration.

Q. What is the influence of route of administration of drug/toxicant on bioavailability?
It is generally in the following order:
IV > oral route >  topical route
Q. Define volume of distribution (Vd)
The total volume of fluid in which a toxic substance must be dissolved to account for the measured plasma concentrations is known as the apparent volume of distribution (Vd). If a compound is distributed only in the plasma fluid, the Vd is small and plasma concentrations are high. Conversely, if a compound is distributed to all sites in the body, or if it accumulates in a specific tissue such as fat or bone, the Vd becomes large and plasma concentrations are low.
Q.  Define total body clearance, term used in kinetic studies of toxicants.
In toxicology, the clearance is a pharmacokinetic measurement of the volume of plasma that is completely cleared off of a substance per unit time. The usual units are mL/min. The total body clearance will be equal to the renal clearance + hepatic clearance + lung clearance.

Flip-flop kinetics

Q. Define flip-flop kinetics
Flip-flop kinetics refers to a situation when the rate of absorption of a compound is significantly slower than its rate of elimination from the body. The compound’s persistence in the body therefore becomes dependent on absorption rather than elimination processes. This sometimes occurs when the route of exposure is dermal.
Q. Define PBTK
It is a physiological based toxico-kinetic (PBTK) model. These models are mathematical stimulation of physiological processes that determine the rate and extent of xenobiotics/toxicant absorption, distribution, metabolism and excretion. The primary difference between physiologic compartmental models and classic compartmental models lies in the basis for assigning the rate constants that describe the transport of chemicals into and out of the compartments. In classic kinetics, the rate constants are defined by the data; thus, these models are often referred to as data-based modelsIn PBTK models, the rate constants represent known or hypothesized biological processes, and these models are commonly referred to as physiologically based toxicokinetic models.

Further Reading

Gupta PK (2018) Illustrative Toxicology with Question bank. 1st Edition. Elsevier, USA

Gupta PK (2016) Fundamentals of Toxicology: Essential concepts and applications. 1st Edition. ISBN-9780128054260, pp 438, BSP/Elsevier, USA

The Merck Veterinary Manual (2016). Chapter “Herbicide Poisoning” by PK GUPTA 11th edition, Merck & Co. Inc Whitehouse Station, NJ, USA  2969-99

The Merck Veterinary Manual (2016). Chapter “Pentachlorophenol Poisoning” by PK GUPTA 11th edition, Merck & Co. Inc Whitehouse Station, NJ, USA  pp 3052-53

Gupta PK (2016) Essential Concepts in Toxicology. Published by PharmaMed Press (A unit of BSP Books Pvt. Ltd), Hyderabad, India pp 362.

Gupta PK (2010) Modern Toxicology, Basis of organ and reproduction toxicity. Vol 1. Published by Pharma  Med Press (A unit of BSP Books Pvt. Ltd). Hyderabad, India pp 1-460.

Gupta PK (2010) Modern Toxicology, Adverse effects of xenobiotics. Vol 2, Published by PharmaMed Press (A unit of BSP Books Pvt. Ltd). Hyderabad, India pp 1-460.

Gupta PK (2010) Modern Toxicology, Immuno and clinicsal toxicology Vol 3. Published by PharmaMed Press (A unit of BSP Books Pvt. Ltd). Hyderabad, India pp 1-340.

Gupta PK (2018) series 2: TOXICOLOGY Question and Answer bank-General Toxicology. https://www.linkedin.com/post/edit/6359300015541837824https://www.linkedin.com/post/edit/6359300015541837824                                                            
                                                                                                                                                        Gupta PK (2018) SERIES 3: TOXICOLOGY Question and Answer bank | Dr Pawan ...
https://www.linkedin.com/.../series-3-toxicology-question-answer-bank-dr-pawan-ku...Jan 26, 2018 - 

https://www.linkedin.com/.../series-4-toxicology-question-answer-bank-dr-pawan-ku...Feb 4, 2018 - Feb 4, 2018 Cont'd from series 3.

https://www.linkedin.com/.../series-5-risk-assessment-toxicology-question-answer-ban...Series 5: Risk Assessment. Cont'd from series 4.

Gupta PK (2018) Series 6: (Multiple choice questions)TOXICOLOGY Question and Answer bank https://www.linkedin.com/pulse/series-6-multiple-choice-questionstoxicology-question-gupta/

Gupta PK (2018) Dr Pawan K (PK) Gupta Series7: Multiple Choice Questions and fill in blanks TOXICOLOGY Question and Answer bank https://www.linkedin.com/pulse/dr-pawan-k-pk-gupta-series7-multiple-choice-questions-gupta/

Gupta PK (2018) Dr Pawan K (PK) Gupta Series8: Fill in blanks TOXICOLOGY Question and Answer bank https://www.linkedin.com/pulse/dr-pawan-k-pk-gupta-s
To be cont’d -Series 10

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