pharmaceutical in the environment case study

1. Presented by:
Sidra Ayub Roll#02
Maryam Hameed Roll#13
Qurrat-ul-Ain Roll#17
Nida Sajjad Roll#39

2.  Any unwanted and undesired substances which
contaminate or deteriorate the quality of air, water and
soil.
 These may directly interact with environment after
their indirect production in various ways.
 These may be present in gaseous,liquid as well as solid
state.

3.  The endocrine system is a complex network of glands and
hormones that regulates many of the body's functions,
including growth, development and maturation, as well as the
way various organs operate.
 including the pituitary, thyroid, adrenal, thymus, pancreas,
ovaries, and testes
 release carefully-measured amounts of hormones into the
bloodstream that act as natural chemical messengers, traveling
to different parts of the body in order to control and adjust
many life functions.

4.  An endocrine-disrupting substance is a compound, either
natural or synthetic which through environmental or
inappropriate developmental exposures alters the hormonal
and homeostatic systems that enable the organism to
communicate with and respond to its environment.
 The number of substances believed to act as endocrine
disruptors is wide and varied, including both natural and
synthetic materials. Concern arises because potential endocrine
disruptors may be present in the environment at very low
levels but still may be able to cause effects.

5. Endocrine disruptors are found also in synthetic
chemicals used as industrial solvents, lubricants, and
their byproducts. These include polychlorinated
biphenyls (PCBs), polybrominated biphenyls (PBBs),
and dixons.
 bisphenol A (BPA) from plastics
 dichlorodiphenyltrichloroethane (DDT) from
pesticides
 vinclozolin from fungizides
 diethylstilbestrol (DES) from pharmaceutical agents.
 Certain metals such as cadmium, mercury, arsenic,
lead, manganese, and zinc also disrupt endocrine
systems.s

6.  They can mimic a natural hormone and lock onto a receptor
with in the cell. The disruptor may give a signal stronger than
the natural hormone, or a signal that occurs at the "wrong"
time.
 They can bind to a receptor within a cell and thus prevent
the correct hormone from binding. The normal signal then fails
to occur and the body fails to respond properly.
The disruptors can interfere or block the way natural
hormones and receptors are made or controlled. This
interference or blockage may occur only if relatively large
doses of the substance are present.

7.  A direct evidence of human susceptibility was found.
 In the 1950s and 1960s pregnant women were prescribed
diethylstilbestrol (DES), a synthetic estrogen, to prevent
miscarriages
 Not only did DES fail to prevent miscarriages, but it also
caused health problems for many of these women's children.
 In 1971, doctors began reporting high rates of unusual vaginal
cancers in teenage girls. Investigations of the girls' environmental
exposures traced the problem to their mothers' use of DES. The
girls also suffered birth defects of the uterus and ovaries, and
immune system suppression.

9. During normal conditions, a carrier
protein transports hormones to the
cell wall; there, it binds to a receptor,
and the hormone and receptor
together bind to a specific region of
a cell's DNA to activate particular
genes.

10. EDCs interfere with this normal hormonal
activity in number of ways.
 They can amplify the effect of normal
hormones by:
1. Mimicking a hormone by binding to its
receptor.
2. By stimulating the production of more
hormone receptors.
 They can weaker the normal hormone
functions by binding to its receptor.

11.  They can prevent hormonal action simply
by occupying the appropriate hormone's
site on the receptor.
 They can bind to carrier proteins and
reduce the availability of these proteins to
transport hormones .
 They can alter the level of endogenous
hormones by accelerating their breakdown
and elimination.

12. Several possible modes of actions have
been cleared up in recent years, most
important of them are mentioned here.

13. “An exogenous agonist is a ligand that
can bind to a receptor like the natural
substrate and “turn it on”.
The potency of an exogenous agonist
depends on:
 Its affinity to the receptor
 Its ability to turn the receptor on
 Concentration of the ligand

14. Well-known examples are:
 Diethylstilbestrol (DES)
 Ethinylestradiol
 Xenoestrogens
 PCBs metabolites
“An antagonist is a ligand that blocks
or diminishes responses provoked by
hormones because the receptor cannot
be activated as usual.”

15. The inhibition of the receptor can be:
 Competitive that can lead to total
deactivation of the receptor.
 Noncompetitive that can result in reduced
reactions performed by the receptor.
Well known examples are:
 linuron
 vinclozolin
 pharmaceutical tamoxifen

16. Change in conc. of hormones indirectly i.e. by
inhibiting or influencing the specific enzymes.
Examples:
 Biosynthesis of estrogens include the
conversion of testosterone to an estrogen
catalyzed by the enzyme aromatase. EDCs can
inhibit this enzyme, leading to higher
testosterone concentrations and to lower
estrogen concentrations.

17.  Hormone metabolism can also be
influenced by induction of hormone-
metabolizing enzymes like the cytochrome
P450-group in the liver.
In receptor-mediated processes, both
components, endogenous ligand and
hormone receptor, own a key function.

18. Example
 “Down-regulation” of steroid hormones
TCDD is an exogenous agonist for the
arylhydrocarbon (Ah)-receptor. Its
activation can have different influences on
the endocrine system by:
(1) An increased degradation rate of estrogen
receptors
(2) Induction of estradiol metabolizing enzymes
(3) Inhibition of gene expression controlled by
estradiol or growth promoters.

20.  Importance of Thyroid
Harmones
 Thyroid hormones are essential for:
 Normal brain development in fetus.
 For the control of metabolism,
 For normal adult physiology.

21.  Environmental pollutants Interfere with the
normal functioning of thyroid hormone and
produce hazaderous effects on:
 development
 metabolism
 adult physiology
 Disturbed Thyroid Harmone signalling
pathways.

22.  Structural Similarity with THs:
 Several Thyroid Disruptors have high degree of
structural resemblance to the thyroxine (T4) and
triiodothyronine (T3) due to which they get attach
to receptor sites instead of THs.
 Interference with regulation:
 Many industrial chemicals and pollutants can
interfere with thyroid function by acting on
different points of regulation of thyroid hormone
synthesis, release, transport through the blood,
metabolism of thyroid hormone.

23.  Perchlorate
 It block uptake of Iodide(form of iodine) in thyroid
cells.As a result T3 and T4 synthesis
decreased.Higher in smoker Women.
 PCBs
 These are lipophilic in nature and accumulate in
fatty tissues.PCBs inhibit TSH receptors and
decrease production of T3 and T4. It reduce T4
circulation in blood.
 Acetochlor(Herbicide)
 It enhance hepatic(liver) metabolism results in
increase metabolism of T3 and T4 unneccesarily

24.  Pentachlorophenol
 T4 transport to target tissues via serum
transport proteins e.g Transthyretin(TTR) but if
pentachlorophenol competitively binds to
serum transport proteins then T4 would not be
transported to target tissue.
 Bisphenol A(BPA)
 At high temprature BPA leach out of plastics
into food.

25.  In Human embryonic kidney cell and
hepatoblastoma cells BPA inhibit T3 binding to
TR .
 Isoflavones,
 especially those found in soy protein (e.g.,
genistein, coumesterol) cause goiter in Human
infants.

26.  Neurodevelopmental toxicity
 Goiter and thyroid diseases are associated with
TH disruption.
 Hypothyroidism
 It results in impaired intellectual development
in childrens or permanent cognitive
deficiencies.

27.  Perchlorate is a known competitive inhibitor of
the sodium-iodide in humans and can inhibit
iodide uptake, leading to the suppression of T3
and T4.
 Effects
 It has been related to lower levels of iodine in
breast milk.As a result of iodine deficiency
neurodevelopmental disorders occur in utero.

28.  In an environment with perchlorate exposure
may have a significant effect on thyroid
hormone production particularly in the
environment of dietary iodine insufficiency

29.  The concept that PCBs can exert a neurotoxic
effect on the developing brain by causing a
state of relative hypothyroidism.
 Polychlorinated biphenyls belong to the class
of organochlorine compounds classified as
persistent organohalogenated pollutants
(POPs)
 Disruption Mechanisms:
 (1)It reducing the ability of thyroid hormones
to bind to transport proteins in the bloodstream

30.  (2)It enhance hepatic metabolism by up-
regulating the sulfotransferases that break
down thyroid hormones in the liver
 (3)It inhibit the production of deiodinases that
allow T4 to be converted to T3
 (4)it act as either an agonist or antagonist at
the site of the cellular thyroid receptor.

31.  PCBs
 BPA(4,4 isopropylidenediphenol)
 PBDEs (polybrominated diphenylethers)

32.  The role of TSH in activating growth and
differentiation of follicular cells have shown
that a prolonged disruption of the pituitary-
thyroid axis is linked to thyroid neoplasia. Two
mechanisms involved in the disruption of the
pituitary thyroid axis are chemically-induced
blocking of thyroid peroxidase and inhibition
of T4 deiodinases, which are known to occur
with TD exposure

33.  Humans are exposed to thousands of chemicals used in several
anthropogenic processes.
 Environmental factors that are under the focus of the scientific
community include organic and chemical solvents, pesticides,
heavy metals, polychlorinated biphenyls (PCBs) and other
persistent organic pollutants (POPs).
 Among environmental pollutants, special concerns have been
raised by endocrine disrupting chemicals (EDCs), which are
hormonally active, synthetic or natural compounds that can
interfere with the normal activity of endocrine system/tissue,
most notably the reproductive endocrine axis.
Human Reproductive Hormone Disruptors
Introduction

34. 1. Adverse reproductive effects have been observed in male
populations, wildlife, and laboratory animals as a
consequence of exposure to hormonally active chemicals.
2. Chemicals could play a role in a number of reproductive
abnormalities in females.
3. Endocrine disrupting chemicals could be contributing to a
population-wide decline in fertility.
4. Exposure to dioxins, toxic byproducts of incineration and
industrial processes, may be associated with fewer male
births.
The hazardous effects

35. 5. Prenatal exposure to some chemicals is associated
with deficits in IQ and memory, neurobehavioral
effects, and delayed neuromuscular development in
children.
Examples:
A. Diethylstilbosterol (DES).
B. Polychlorinated biphenyls (PCBs).
C. Polybrominated biphenyls (PBB).
D. Chloroform.
E. Dioxins and furans.
F. Pesticides

36. Diethylstilbosterol (DES):
 Consider one of the most famous endocrine disruptors.
 A synthetic estrogen prescribed to pregnant women in the
1950s and 1960s to prevent miscarriage.
 Ultimately, more than 300 cases of CCA(clear cell
endocarcinoma) have been documented in women
exposed in utero to DES.
Polychlorinated biphenyls (PCBs):
Uses:
• paints.
• Lubricants
• Plastic water and baby bottles, food and beverage can
linings and dental sealants ate the most commonly
encountered uses of this chemical.

37. 1. The children born to these prenatally exposed
mothers have the following more than unexposed
ones:
1. Sperm with abnormal morphology, reduced
motility, and reduced strength.
2. Intrauterine growth retardation (IUGR).
3. Abnormal skin pigmentation.
4. Delayed, developmental milestones.
5. Lower (IQs).
2. Women who had eaten PCB-contaminated fish
before and during pregnancy documented dose-
related delays in development and reductions in
intellect in their infants in the absence of any overt
symptoms.

38. PESTICIDES:
Reproductive effects:
Effects on the reproductive system or on the ability to
produce healthy offspring.
Teratogenic:
Causes birth defects if used it during their
pregnancy.
• The aberrant production of ovarian steroid hormones
(progesterone, estradiol, and androgens) can disrupt normal
folliculogenesis.
• It follows that environmental agents and pathogens that
mimic the actions of ovarian steroids via the activation of
steroid hormone receptors, could disrupt follicle
development and/or ovulation.
Anti-androgenic endocrine disruptors:
 Vinclozolin.
 DDE.

39. Hazardous effects:
• Clear cell adenocarcinoma (CCA) of the
vagina and cervix .
• Irregular uterine bleeding.
• Recurrent abortion.
• Intrauterine growth retardation.
• Abnormalities within the reproductive,
cardiovascular, neuroendocrine, and immune
systems.
Effects on the ovary and female reproductive function:

40. BREAST CANCER
A review of known risk factors includes the possible
influence of exogenous estrogens and several that are related to
levels of the naturally synthesized estrogen estradiol. Early onset
of menstruation, late menopause, never having given birth and
never having breastfed contribute to the risk by elevating a
woman's lifetime exposure to estradiol.
Another risk factor, being older than 50, probably reflects
older women's long-term exposure to this hormone.
Additionally, the increased odds of the disease that have
been found among women with diets high in animal fat and with
high levels of alcohol consumption may be explained by the fact
that fat tissue can manufacture estrogen, and alcohol can
increase the hormone's production. These are not the only risk
factors for the disease (high-dose exposure to X rays also plays
an important role). Researchers hypothesize that if an excess of
natural estrogen can be harmful, prolonged exposure to man-
made estrogens might pose similar threats.

42.  Eat lower on the food chain.
 Eat deep-water fish (avoid sword fish, tuna and
shark and all farm raised fish)
 In general, substitute natural products for synthetic
products whenever possible.
 Eat fresh organic products as meat and milk free from
rBGH (Recombinant Bovine Growth Hormone).
 Buy products at your local Farmers' Market or join a
buying club.
 Use fewer processed, prepackaged foods whenever
possible.
 Do not give young children soft plastic toys, since
these leach potential endocrine disrupting chemicals.
Measures to lower the exposure to endocrine disruptors

43.  Avoid smoke.
 Avoid use chemicals or any pesticides.
 Avoid use makeup, hair sprays & coloring
products or nail polish.
 Avoid use strong chemicals, glues, paints, nail
polish remover, floor & carpet cleaners.
 Avoid heat food or eat hot food in plastic
containers, even the ones frozen dinners now
come in.
 Avoid products with hydrogenated, partially
hydrogenated fats.
 Avoid stay in places that smell of chemicals.