Toxicity and Human Health

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Toxicity and Human Health

• Inneke Hantoro

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Toxicity

• Toxicity is the potential of a chemical to induce
  an adverse effect in a living organism e.g., man.

How a toxicant enters an organism
Toxicity
How it interacts with target molecule
How organism deals with the insult
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• The induction of toxic effects largely depends on
  the disposition of the substances concerned.

Interaction of a substance with a living organism
Kinetic Phase
absorption, distribution, metabolism, and
excretion ? the fate of substance in the body
the body has a number of defense mechanisms
at various levels of the kinetic phase,
metabolism excretion
Dynamic Phase
interactions of the toxicant within the organism
and describes processes at organ, tissue,
cellular, and molecular levels
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Potential stages in the development of toxicity
after chemical exposure
Toxicant
Delivery
Interaction with target molecule
Alteration of biological environment
Cellular dysfunction, injury
T O X I C I T Y
Dysrepair
Klassen (2001)
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Step 1Delivery

• Theoretically, the intensity of a toxic effect
  depends primarily on the concentration and
  persistence of the ultimate toxicant at its site
  of action.
• The ultimate toxicant is the chemical species
  that reacts with the endogenous target molecule
  (e.g., receptor, enzyme, DNA, protein, lipid) or
  critically alters the biological (micro)
  environment, initiating structural and/or
  functional alterations that result is toxicity.

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• Factors that can facilitate the accumulation of
  ultimate toxicants

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• Absorption
• Absorption is the transfer of a chemical from the
  site of exposure, usually an external or internal
  body surface (e.g., skin, mucosa of the
  alimentary and respiratory tracts), into the
  systemic circulation.
• Presystemic Elimination
• During transfer from the site of exposure to the
  systemic circulation, toxicants may be
  eliminated.

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• Distribution to and away from the target
• Mechanisms facilitating distribution to a target
• the porosity of the capillary endothelium
• specialized membrane transport
• accumulation in cell organelles
• reversible intracellular binding

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• Mechanisms Opposing Distribution to a Target
• Distribution of toxicants to specific sites may
  be hindered by several processes, including
• binding to plasma proteins
• specialized barriers
• distribution to storage sites such as adipose
  tissue
• association with intracellular binding proteins
  export from cells

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• Excretion. Excretion is the removal of
  xenobiotics from the blood and their return to
  the external environment.
• Reabsorbtion.

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• Toxication
• Biotransformation to harmful products is called
  toxication or metabolic activation.
• With some xenobiotics, toxication confers
  physicochemical properties that adversely alter
  the microenvironment of biological processes or
  structures.
• For example, oxalic acid formed from ethylene
  glycol may cause acidosis and hypocalcaemia as
  well as obstruction of renal tubules by
  precipitation as calcium oxalate.

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• Detoxication
• Biotransformation that eliminates an ultimate
  toxicant or prevents its formation is called
  detoxication.

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The absorption of toxicants

• Process by which the toxicants cross the
  epithelial cell barriers.
• Route of absorption
• Skin
• Respiratory
• Digestive

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The absorption of toxicants

• Absorption through skin, lung or intestinal
  tissue is followed by passage into the
  interstitial fluid.
• Interstitial fluid (15), intracellular fluid
  (40), blood plasma (8)
• Toxicants is absorbed enters the lymph or blood
  supply and is mobilized to other parts of the
  body.
• Toxicant can enter local tissue cells.

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Integumentary System Route

• Skin, hair, nails, mammary glands. Skin is the
  largest organ in the body.
• Epidermis.
• Avascular, keratinized stratum corneum, 15-
• 20 cells thick, provides most toxicant
  protection.
• Dermis.
• Highly vascularized nerve endings, hair
• follicles, sweat and oil glands.
• Hypodermis.
• Connective and adipose tissue.

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Skin
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Respiratory System Route

• Skin stratified squamous epithelial tissue
• Respiratory system squamous epithelium, cilated
  columnar and cuboidal epithelium
• Non-keratinized, but cilated tissues and
  muscus-secreting cells provide mucociliary
  escalator

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• Nasopharyngeal.
• Nostrils, nasopharynx, oropharynx,
• laryngopharynx.
• Hairs and mucus trap gt5 µm particulates.
• Tracheobronchial.
• Trachea, bronchi, bronchioles cillial action.
• Luminal mucus aerosols and gases.
• Pulmonary
• Alveoli - high surface area gas exchange with
  
• cardiovascular system.

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Digestive System Route

• Mouth, oral cavity, esophagus, stomach, small
• intestine, rectum, anus.
• Residence time can determine site of toxicant
• entry/injury.
• Mouth (short) small intestine (long).
• Absorption of toxicants can take place
  anywhere, but much of the tissue structure in the
  digestion system is specially designed for
  absorption.

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Digestive System Route

• Tissue differentiation.
• Mucosa
• Avascular, s. squamus or columnar
• epithelium.
• In some regions villi and microvilli
• structure aids in absorption
• (high surface area).
• Submucosa
• Blood, lymph system interface.
• Muscularis (movement).
• Serosa (casing).

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Distribution of toxicants in the body

• Lymphatic system
• Lymph capillaries, nodes, tonsils, spleen,
  thymus, lymphocytes
• Drain fluids from systems
• Slow circulation
• Cardiovascular system
• Heart, arterial and venous vessels, capillaries,
  blood
• Fast circulation
• Major distribution by blood

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• In blood system, major toxicant transport medium
• Erythrocytes (red blood cell)
• Leukocytes (white blood cell)
• Platelets (thrombocytes)
• Plasma (non-cellular fluid)

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Factors affecting Distribution

• Physical or chemical properties of toxicants
• Concentration gradient (volume of distribution)
• Cardiac output to the specific tissues
• Detoxication reactions (protein binding)
• Tissue sensitivity to the toxicant (adipose
  tissue, receptors)
• Barriers that inhibit migration (blood-brain,
  placental)

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Step 2Reaction of toxicants with the target
molecule
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Step 3 alteration of the regulatory or
maintenance function of the cell
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Storage of toxicants

• Accumulation of toxicants in specific tissues.
• Binding to plasma proteins.
• Albumin most abundant and common binder
• Storage in bones.
• Heavy metals, like Pb
• Storage in liver.
• Blood flow, biotransformation
• Storage in the kidneys.
• Storage in fat.
• Lipophilic compounds

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Target Organ Toxicity

• Adverse effects or disease states manifested in
  specific organs in the body
• High cardiac output higher exposure
• Organs each have specialized tissues and cells
• Differentiated cellular processes and receptors
• Toxicants and metabolites may have specific
  reactive pathways

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Target Organ Toxicity

• Toxicants do not affect all organs to the same
  extent
• A toxicant may have several sites of action and
  target organs
• Multi-toxicant exposure may target the same organ
• The target organ may not be the site for storage

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The main target organs for the systemic toxicity
of xenobiotics are

• Skin, mucous membrane
• Lungs
• Liver, kidney
• Bone marrow
• Immune system
• Nervous system (central peripheral)
• Cardiovascular system
• Reproductive system
• Muscle and bones

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Why an organ or tissue is sensitive to a
particular toxicants?

• The toxicants accumulates preferably in this
  organ/tissue
• Inactive pro-toxicants is activated in this
  organ/ tissue by phase I enzymes in high
  concentration
• The repairing system in the tissue is either
  less-developed or absent to the toxicant
• This tissue has receptors specific to this
  toxicant receptors on the cell membrane
• This tissue has an elevated physiological
  sensitivity to this toxicant

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Variability of toxic response

• Individual-related (subjective)
• Living and working environment-related (objective)

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Factors influencing the intensity of toxic
response

• Age
• Gender
• Endocrine situation
• Nutritional habits
• Hereditary, previous disease therapy
• Etc.

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Types of toxic response

• Local
• Occurring only at the site of exposure of the
  organisms to the potentially toxic substance
  (skin, lungs, digestive tracts)
• Systemic
• Revealing itself after distribution of the
  toxicant via the bloodstream around the affected
  organism including the target organ or tissue,
  distinct from the absorption site.

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According to the nature of their adverse effect
on the target organs, the toxicants can be
divided as (1)

• Irritants
• Cause damage to the eyes mucous membranes, ex
  bromine, chlorine, ammonia, etc.
• Corrosive substances
• Corrode the skin mucous membranes
• Substances that cause toxic pulmonary edema
• Chlorine, ammonia, nitrogen oxide
• Blockers of mitochondrial respiratory enzymes
• Cyanides, salicylic acid, gossypol

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According to the nature of their adverse effect
on the target organs, the toxicants can be
divided as (2)

• Inhibitors of thiol enzymes
• Heavy metals
• Blockers of Krebs cycle (citrate cycle)
• fluoroacetates
• Emetic substances
• Apromorphine, zinc, copper sulfate
• Neurotoxicants
• Cardiotoxicants
• Selectively damage the heart
• Ex cardioglucosides, digitoxin, aconitine, etc.

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According to the nature of their adverse effect
on the target organs, the toxicants can be
divided as (3)

• Hepatotoxic substances
• Damage the liver
• Carbon tetrachloride, chloroform,etc.
• Nefrotoxic substances
• Damage the kidneys
• Mercury, chlorine, carbon tetrachloride, lead
• Substances that damage the bone marrow and blood
  cells
• Nirobenzene, benzene, etc.

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According to the nature of their adverse effect
on the target organs, the toxicants can be
divided as (4)

• Asphyxiants
• Substances that cause a reduction of bloods
  ability to bind and transport oxygen
• Anticoagulants
• Substances that disturb blood coagulation
• Dicumarine, heparin, etc.
• Hemolytic substances
• Mushroom toxicants, phenyl-hydrazine, saponins,
  etc.
• Histamine and antihistaminic compounds

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Based on the character of damage of a cell/ an
organism, the toxic effects can be grouped as (1)

• Generally toxic
• Damage of the organism as a whole
• Dystrophic
• Causing the aging cells or tissues
• Genotoxic
• Alteration of the genetic material (DNA, RNA)
• Mutagenic
• Generation of irreversible changes in the
  hereditary materials (chromosomes, genes) of an
  organism

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Based on the character of damage of a cell/ an
organism, the toxic effects can be grouped as (2)

• Carcinogenic
• Genaration of malignant tumors
• Gonadotropic
• Harming and inhibiting the development of the
  germ cells
• Teratogenic
• Evoking disorders in the embryonal development of
  an organism
• Sensibilizating
• Making an organism ultrasensitive to this
  compound, resulting in allergic reactions and
  diseases

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According to the final result, toxic responses
can be grouped as

• Direct injury of cell or tissue
• Biochemical damage
• Neurotoxicity
• Immunotoxicity
• Teratogenicity
• Genetic toxicity
• Carcinogenicity
• Endocrine disruption

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Direct injury of cell or tissue

• Decomposition of cells (necrosis)
• An irreversible process consisting of
  degeneration of the cell, fragmentation of the
  nucleus, and denaturation of the cellular
  proteins.
• The cell disperses, accumulates liquid and its
  content flows out.

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Direct injury of cell or tissue

• Mechanism
• The formation of an intermediate that reacts with
  definite cell components like structural
  proteins.
• Examples
• CN- ion or Pb can interact with the respiratory
  system of a cell --- leads to the death of a cell
• Strong alkalis or acids
• Strong oxidizers ozone (O3), Cl2, Br2, F2 are
  very harmful to human and microorganisms.

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Direct injury of cell or tissue

• Apoptosis the programmed cell death
• Normal process for tissue renewal but it can be
  evoked by certain substances
• Example trans-resveratrol (in grape wines) and
  its relatives (glucosides, etc).

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Biochemical damage

• Biochemical injury cause
• Degeneration of a single cell
• Influencing vital function of metabolism such as
  respiration
• The death of organism
• Disruption of cell metabolism
• Deficiency of several organs

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Neurotoxicity

• Compounds that have a toxic effect on the nervous
  system
• Toxicants of the central nervous system (CNS)
• Toxicants of the peripheral nervous system (PNS)
• Toxicants of a combined effect

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Neurotoxicity

• Many toxic compounds can cause serious brain
  impairment. Based on the mechanism of their
  effect, toxicants that have undesirable effect to
  the brain can be grouped
• Neurotoxic compounds
• These compounds can disturb the function of
  nervous system
• Mercury, acrylamide, hexane, CO2,
  methyl-n-butylketone.

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Neurotoxicity

• CNS inhibitor
• Chlorinated hydrocarbons, benzene, aceton, dietyl
  eter
• Psychomimetics
• They can disturb psychical activities
• Mescalin, phenylethylamine derivatives, indole
  derivaties
• Compounds that inhibiting the respiration center
• Narcotics, hydrocarbons

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Neurotoxicity

• Convulsion toxicants
• Convulsion in central origin
• Organophosphorus pesticide
• Toxicants, paralyzing transmission of nerve
  impulses to the muscle
• Botulinin
• Toxicants, paralyzing transmission of nerve
  impulses in the nerve
• Tetrodotoxin

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Neurotoxicity

• Neuroparalytic poisons
• anticholinesteratic
• Toxicants, acting with mediators or synaptic
  poisons
• Adrenaline, ephedrine, hydrazines, etc.

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Dose Response Dose Effect Relationships
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Dose response

• The intensity of a biological response is
  proportional to the concentration of the
  substance in the body fluids of the exposed
  organism.
• The concentration of the substance in the body
  fluids, in turn, is usually proportional to the
  dose of the substance to which the organism is
  subjected.
• As the dose of a substance is increased, the
  severity of the toxic response will increase
  until at a high enough dose the substance will be
  lethal ? individual dose-response

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• There will be a range of doses over which the
  organisms respond in the same way to the test
  substance. In contrast to the graded individual
  dose-response, this type of evaluation of
  toxicity depends on whether or not the test
  subjects develop a specified response, and is
  called quantal population response.
• To specify this group behavior, a plot of percent
  of individuals that respond in a specified manner
  against the log of the dose is generated.

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Lethal dose 50 (LD50)

• A widely used statistical approach for estimating
  the response of a population to a toxic exposure
  is the Effective Dose or ED.
• Generally, the mid-point, or 50, response level
  is used, giving rise to the ED50 value.
  However, any response level, such as an ED01,
  ED10 or ED30 could be chosen.
• Where death is the measured end-point, the ED50
  would be referred to as the Lethal Dose 50 (LD50).

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• The TD50 (toxic dose such as liver injury) is
  the statistically determined dose that produced
  toxicity in 50 of the test organisms.
• If the toxic response of interest is lethality,
  then LD50 is the proper notation.

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The Margin of Safety

• The margin of safety of a substance is the range
  of doses between the toxic and beneficial
  effects to allow for possible differences in the
  slopes of the effective and toxic dose-response
  curves, it is computed as follows
• Margin of Safety (MS) LD1 / ED99
• LD1 is the 1 lethal dose level and ED99 is the
  99 effective dose level.

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Threshold Approaches

• The threshold (T) represents the dose below which
  no additional increase in response is observed.
• NOAEL (No Observed Adverse Effect Level)
• is the highest dose at which none of the
  specified toxicity.
• LOAEL (No Observed Adverse Effect Level)
• is the lowest dose at which toxicity was
  produced.

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• Subchronic exposure can last for different
  periods of time, but 90 days is the most common
  test duration.
• The principal goals of the subchronic study are
  to establish a NOAEL and to further identify and
  characterize the specific organ or organs
  affected by the test compound after repeated
  administration. One may also obtain a lowest
  observed adverse effect level (LOAEL) as well as
  the NOAEL for the species tested.

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Dose response curve

• This figure is designed to illustrate a typical
  doseresponse curve with points E to I indicating
  the biologically determined responses. The
  threshold dose is shown by T, a dose below which
  no change in biological response occurs. Point E
  represents the point of departure (POD), the dose
  near the lower end of the observed doseresponse
  range, below which, extrapolation to lower doses
  is necessary (EPA, 2005b). Point F is the highest
  nonstatistically significant response point,
  hence it is the no observed adverse effect
  level (NOAEL) for this example. Point G is the
  lowest observed adverse response level (LOAEL).
  Curves AD show some options for extrapolating
  the doseresponse relationship below the range of
  biologically observed data points, POD, point E.

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• NOAELs have traditionally served as the basis for
  risk assessment calculations, such as reference
  doses or acceptable daily intake (ADI) values.
• Reference doses (RfDs) or concentrations (RfCs)
  are estimates of a daily exposure to an agent
  that is assumed to be without adverse health
  impact in humans.
• RfD NOAEL / (UF x MF)

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Tolerable daily intake (TDI)

• Tolerable daily intakes (TDI) can be used to
  describe intakes for chemicals that are not
  acceptable but are tolerable as they are
  below levels thought to cause adverse health
  effects.
• These are calculated in a manner similar to ADI.
• In principle, dividing by the uncertainty factors
  allows for interspecies (animal-to-human) and
  intraspecies (human-to-human) variability with
  default values of 10 each.
• An additional uncertainty factor is used to
  account for experimental inadequacies

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• If only a LOAEL value is available, then an
  additional 10-fold factor commonly is used to
  arrive at a value more comparable to a NOAEL.
• For developmental toxicity endpoints, it has been
  demonstrated that the application of the 10-fold
  factor for LOAEL-to-NOAEL conversion is too
  large.
• Traditionally, a safety factor of 100 would be
  used for RfD calculations to extrapolate from a
  well-conducted animal bioassay (10-fold factor
  animal to human) and to account for human
  variability in response (10-fold factor
  human-to-human variability).

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Acceptable Daily Intake

• Safety of exposures is estimated based on the
  NOAEL adjusted by a series of population
  susceptibility factors to provide a value for the
  Acceptable Daily Intake (ADI). The ADI is an
  estimate of the level of daily exposure to an
  agent that is projected to be without adverse
  health impact on the human population.
• ADI NOAEL / (UF x MF)
• where UF is the uncertainty factor and MF is the
  modifying factor.

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• UF and MF provide adjustments to ADI that are
  presumed to ensure safety by accounting for
  uncertainty in dose extrapolation, uncertainty in
  duration extrapolation, differential
  sensitivities between humans and animals, and
  differential sensitivities among humans (e.g.,
  the presumed increased sensitivity for children
  compared to adults).
• Thus, for a substance that triggers all four of
  the uncertainty factors indicated previously, the
  calculation would be ADI NOAEL/10,000.

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• In some cases, for example, if the metabolism of
  the substance is known to provide greater
  sensitivity in the test organism compared to
  humans, an MF of less than 1 may be applied in
  the ADI calculation.
• The ADIs are used by WHO for pesticides and food
  additives to define the daily intake of
  chemical, which during an entire lifetime appears
  to be without appreciable risk on the basis of
  all known facts at that time.

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• To reduce uncertainty in calculating RfDs and
  ADIs, there has been a transition from the use of
  traditional 10-fold uncertainty factors to the
  use of data-derived and chemical-specific
  adjustment factors.
• Such efforts have included reviewing the human
  pharmacologic literature from published clinical
  trials

Toxicokinetic (TK) and toxicodynamic (TD)
considerations inherent in interspecies and
interindividual extrapolations
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Benchmark dose lower confidence limit (BMDL)

• BMD The doseresponse is modeled and the lower
  confidence bound for a dose at a specified
  response level benchmark response (BMR) is
  calculated.
• The BMD is used as an alternative to the
  NOAEL/LOAEL approach for a more quantitative way
  of deriving regulatory levels for health effects
  assumed to have a nonlinear (threshold-like) low
  doseresponse relationship.
• The BMR is usually specified at 1, 5, or 10.
• The BMDx (with x representing the percent
  benchmark response) is used as an alternative to
  the NOAEL value for reference dose calculations.
• RfD BMDx / (UF x MF)

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• The BMD approach involves modeling the
  doseresponse curve in the range of the
  observable data, and then using that model to
  interpolate an estimate of the dose that
  corresponds to a particular level of response,
  e.g., 5 or 10 for quantal data, or some
  predefined change in response from controls for
  continuous data.

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Hormeosis

• Hormesis is a dose-response phenomenon
  characterized by a low dose beneficial effect and
  a high dose toxic effect, resulting in either a
  J-shaped or an inverted U-shaped dose-response
  curve.
• A hormetic substance, therefore, instead of
  having no effect at low doses, as is the case for
  most toxins, produces a positive effect compared
  to the untreated subjects.

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Thank You