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Toxicity and Human Health


Human Health

          Inneke Hantoro
 Toxicity is the potential of a chemical to induce
 an adverse effect in a living organism e.g.,
                How a toxicant enters
                an organism

 Toxicity       How it interacts with
                target molecule

                How organism deals
                with the insult
The induction of toxic effects largely depends
on the disposition of the substances

 Interaction of a substance with a living organism

                    absorption, distribution,
 Phase           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      interactions of the toxicant within the organism
 Phase           and describes processes at organ, tissue,
                        cellular, and molecular levels
     Potential stages in the development of toxicity after
                                     chemical exposure


            Interaction                   Alteration
            with target                  of biological
             molecule                    environment

                            Cellular                     T
                          dysfunction,                   O
                             injury                      X
Klassen (2001)                                           Y
 Step 1:

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
Factors that can
facilitate the
accumulation of
ultimate toxicants
  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
Distribution to and away from the
  Mechanisms facilitating distribution to a
    the porosity of the capillary endothelium
    specialized membrane transport
    accumulation in cell organelles
    reversible intracellular binding
Mechanisms Opposing Distribution to
a Target
Distribution of toxicants to specific sites
may be hindered by several processes,
  binding to plasma proteins
  specialized barriers
  distribution to storage sites such as adipose
  association with intracellular binding proteins
  export from cells
Excretion. Excretion is the removal of
xenobiotics from the blood and their
return to the external environment.
  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.
Biotransformation that eliminates an
ultimate toxicant or prevents its formation is
called detoxication.
The absorption of toxicants

 Process by which the toxicants cross
 the epithelial cell barriers.
 Route of absorption:
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.
Integumentary System Route
  Skin, hair, nails, mammary glands. Skin is the
  largest organ in the body.
  – Avascular, keratinized stratum corneum, 15-
    20 cells thick, provides most toxicant
  – Highly vascularized; nerve endings, hair
    follicles, sweat and oil glands.
  – Connective and adipose tissue.
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
– Nostrils, nasopharynx, oropharynx,
– Hairs and mucus; trap >5 μm particulates.
– Trachea, bronchi, bronchioles; cillial
– Luminal mucus aerosols and gases.
– Alveoli - high surface area gas exchange
 cardiovascular system.
Digestive System Route
  Mouth, oral cavity, esophagus, stomach, small
  intestine, rectum, anus.
  Residence time can determine site of toxicant
  – 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
Digestive System Route

             Tissue differentiation.
             – Avascular, s. squamus or columnar
             – In some regions villi and microvilli
                  structure aids in absorption
                  (high surface area).
             – Blood, lymph system interface.
             Muscularis (movement).
             Serosa (casing).
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,
    Fast circulation
  Major distribution by blood
In blood system, major toxicant
transport medium:
 Erythrocytes (red blood cell)
 Leukocytes (white blood cell)
 Platelets (thrombocytes)
 Plasma (non-cellular fluid)
Factors affecting Distribution:
   Physical or chemical properties of
   Concentration gradient (volume of
   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)
Step 2:
Reaction of
with the
Step 3: alteration of the regulatory or
maintenance function of the cell
Storage of toxicants
 Accumulation of toxicants in specific tissues.
 Binding to plasma proteins.
    Albumin most abundant and common
 Storage in bones.
    Heavy metals, like Pb
 Storage in liver.
    Blood flow, biotransformation
 Storage in the kidneys.
 Storage in fat.
    Lipophilic compounds
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
 Differentiated cellular processes and
 Toxicants and metabolites may have
 specific reactive pathways
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
The main target organs for the
systemic toxicity of xenobiotics are:
  Skin, mucous membrane
  Liver, kidney
  Bone marrow
  Immune system
  Nervous system (central & peripheral)
  Cardiovascular system
  Reproductive system
  Muscle and bones
Why an organ or tissue is sensitive to a
particular toxicants?
   The toxicants accumulates preferably in this
   Inactive pro-toxicants is activated in this
   organ/ tissue by phase I enzymes in high
   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
Variability of toxic response

 Individual-related (subjective)
 Living and working environment-
 related (objective)
Factors influencing the intensity of
toxic response
  Endocrine situation
  Nutritional habits
  Hereditary, previous disease &
Types of toxic response
   Occurring only at the site of exposure of
   the organisms to the potentially toxic
   substance (skin, lungs, digestive tracts)
   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.
According to the nature of their adverse effect
on the target organs, the toxicants can be
divided as:         (1)
       Cause damage to the eyes & mucous
       membranes, ex: bromine, chlorine, ammonia,
  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
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)
    Emetic substances
       Apromorphine, zinc, copper sulfate
       Selectively damage the heart
       Ex: cardioglucosides, digitoxin, aconitine,
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.
According to the nature of their adverse effect
on the target organs, the toxicants can be
divided as:         (4)

       Substances that cause a reduction of blood’s
       ability to bind and transport oxygen
       Substances that disturb blood coagulation
       Dicumarine, heparin, etc.
    Hemolytic substances
       Mushroom toxicants, phenyl-hydrazine,
       saponins, etc.
    Histamine and antihistaminic compounds
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
     Causing the aging cells or tissues
     Alteration of the genetic material (DNA, RNA)
     Generation of irreversible changes in the
     hereditary materials (chromosomes, genes) of
     an organism
Based on the character of damage of a cell/
an organism, the toxic effects can be grouped
as (2):

      Genaration of malignant tumors
      Harming and inhibiting the development of
      the germ cells
      Evoking disorders in the embryonal
      development of an organism
      Making an organism ultrasensitive to this
      compound, resulting in allergic reactions and
According to the final result, toxic
responses can be grouped as:
  Direct injury of cell or tissue
  Biochemical damage
  Genetic toxicity
  Endocrine disruption
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.
Direct injury of cell or tissue

   The formation of an intermediate that
   reacts with definite cell components like
   structural proteins.
     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.
Direct injury of cell or tissue

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

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

  CNS inhibitor:
    Chlorinated hydrocarbons, benzene,
    aceton, dietyl eter
    They can disturb psychical activities
    Mescalin, phenylethylamine
    derivatives, indole derivaties
  Compounds that inhibiting the respiration
    Narcotics, hydrocarbons
 Convulsion toxicants
   Convulsion in central origin
   Organophosphorus pesticide
 Toxicants, paralyzing transmission of
 nerve impulses to the muscle
 Toxicants, paralyzing transmission of
 nerve impulses in the nerve

 Neuroparalytic poisons:
 Toxicants, acting with mediators or
 synaptic poisons:
   Adrenaline, ephedrine, hydrazines, etc.
    Dose – Response
Dose – Effect Relationships
Dose response
 The intensity of a biological response is
 proportional to the concentration of the
 substance in the body fluids of the exposed
 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
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
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).
The TD50 (toxic dose – such as liver injury)
is the statistically determined dose that
produced toxicity in 50% of the test
If the toxic response of interest is lethality,
then LD50 is the proper notation.
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.
Threshold Approaches
 The threshold (T) represents the dose below
 which no additional increase in response is
   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
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.
Dose response curve
This figure is designed to illustrate a
typical dose–response 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 dose–response
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 A–D show some
options for extrapolating the dose–
response relationship below the
range of biologically observed data
points, POD, point E.
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)
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
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
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
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
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
Thus, for a substance that triggers all four of the
uncertainty factors indicated previously, the
calculation would be ADI = NOAEL/10,000.
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”.
     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
     Such efforts have included reviewing the human
     pharmacologic literature from published clinical

Toxicokinetic (TK) and toxicodynamic (TD) considerations inherent in
           interspecies and interindividual extrapolations
Benchmark dose lower confidence
limit (BMDL)
 BMD: The dose–response 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 dose–response
 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)
The BMD approach involves modeling the
dose–response 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.

 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.
Thank You…

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