Chapter II

Literature Review
2.1 Transfluthrin
Pesticides are widely use in human life, one type of
insecticide pesticides that can be used to control pests such as
mosquitoes. (Lasut, et al., 2000). Examples of these insecticides
are transfluthrin. Transfluthrin, E-ISO also called benflutrin
(Bayer), NAK 4455, including a pyrethroid chemical group with
molecular formula C15H12Cl2F4O2. While naming chemical is as
follows (WHO, 2006) :
IUPAC: 2,3,5,6-tetrafluorobenzyl (1R,3S)-3-(2,2-dichlorovinyl)-2,2dimethylcyclopropanecarboxylate
CA:
(1R-trans)-(2,3,5,6-tetrafluorophenyl)methyl

3-(2,2-

dichloroethenyl)-2,2- Dimethylcyclopropanecarboxylate

Figure 1. Structural formula of Transflutrin (WHO, 2006).

Transflutrin has physical and chemical properties are described in Table

1a

Tabel 1a. Sifat Fisik Transflutrin

Rumus Molek1ul

C15H12Cl2F4O2

Massa Molar

371.15 g mol1

Bentuk Fisik

Kristal tidak berwarna

Densitas

1.507 g/cm3 (23 C)

Titik Cair

32 C, 305 K, 90 F

Titik Didih

135

at

0.1

mmHg

~ 250 C at 760 mmHg

Kelarutan dalam Air
Kelarutan

dalam

5.710.5 g/L
hexane,

isopropanol,

toluene,

dichloromethane

Sangat larut

Tabel 1b. Sifat Kimia Transflutrin

PARAMETER

NILAI DAN KONDISI

Tekanan

9 x 10-4 Pa pada 20C

penguapan

Titik

lebur,

titik

uap dan/atau suhu

dekomposisi
Kelarutan

(%)

97.8

Titik lebur: 32oC

Titik uap: 242oC

dalam

parsisi

pada oktanol/air

METODE

OECD 104

Kalorimeter
98

scanning
differensial,
OECD 103

Suhu dekomposisi: > 204oC

air

Koefisien

KEMURNIAN

0.057 mg/l pada 20C

97.8

OECD 105

Log KOW=5.46 pada 20oC

97.8

OECD 107

Sesuai dengan
Waktu paruh= lebih dari 1

EPA

tahun pada 25oC pada pH 5

Karakteristik

and pH 7

Minimal 94

hidrolisis

Guideline,
Subdivision

Waktu paruh =14 hari pada

N,

25oC pada pH 9

1611

(1982)
Hampir tidak dipengaruhi
Karakteristik
Fotolisis

secara
degradasi
dapat

langsung
foto,
diperoleh

oleh
tetapi

97.8

dari

degradesi fotokimia alami

Karakteristik

Tidak

menampakkan

Penguraian

komponen asam-basa di air

98.4

Metode

titrasi,

OECD 112

Transfluthrin is a fast-acting insecticide-pyrethroid with low

persistency. Transfluthrin often used in the residential area to protect
against flies, mosquitoes and cockroaches. This is a relatively volatile
substances and act as agents of skin contact and inhalation agents.
Transfluthrin, if the use is not in accordance with product instructions,
can cause poisoning symptoms include restlessness, anxiety, tremors,
seizures, skin allergies, sneezing, nasal symptoms and irritation. To
date, there is no specific antidote, but symptomatic treatment is
antihistamines to control allergy that appears as the symptoms.
Transflutrin which is included in the one of endocrine disrupting
chemicals are fat soluble molecule. Tranfluthrin mechanisms as one of
endocrine-disrupting chemicals the damage of DNA polymorphism.
Endocrine-disrupting

chemicals

according

to

the

Environmental

Protection Agency (EPA) is an exogenous agent that interferes with the

secretion of transport metabolism secretion binding action. Exposure to
endocrine-disrupting chemicals has effects on various body systems,
electrolyte imbalance between diet and activity, increasing the risk of
obesity and the diseases associated with obesity such as diabetes and

cardiovascular

disease.

Immune

system,

cognitive

function

and

personality disorders increased in line with the risk of the emergence of

cardiovascular

disease

also

correlated

with

endocrine-disrupting

chemicals. (International Chemical Secretary, 2008)

II.2 Endocrine Disruptors Chemicals

Today around the world, especially in developed countries
discussion about environmental pollution problems be caused by
hormone disruptors, or in the country known as Japan Kankyo hormone
/ hormone environment is becoming an issues. Even dioxin, one type of
hormone disruptors, referred to by the Japanese as the most potent
toxins ever created by humankind. The world's attention to the dangers
of chemicals only realized in 1962 by Rachel Carson in her book Silent
Spring that reminded of the dangers of the use of pesticides,
especially

chemicals

such

as

DDT

which

are

bioacumulative

(accumulate in living body continuously and can not be removed from

the body).
According to the U.S. EPA endocrine disruptor is defined as "an
exogenous agent that interferes with synthesis, secretion, transport,
metabolism, binding action, or elimination of natural blood-borne
homones that are present in the body and are responsible for
homeostasis, reproduction , and developmental process "or in another
sense an exogenous agent that interferes with the synthesis, secretion,
transport, metabolism, binding

action

or elimination of

natural

hormones in the blood circulating in the body and is responsible for the
process of homeostasis, reproduction and developmental processes.
(Diamanti et al, 2009)
Since the development of the chemical industry in the 40s,
thousands of chemicals are produced and released into the air and
water. Currently, chemical substances contaminated even in the
remote parts of the world. Today, more apparent harm from the
combined results of chemical used in industrial processes, consumer

products and pesticides. A number of studies and data show that the
number of substances that have the potential to disrupt the normal
working

of

hormones

the

body,

profoundly affect

fertility

and

reproduction, Intelligence, immune / immunity, and ultimately survival

II.2.1 Endocrine Disruptors Mechanisms

The body has three main systems, the nervous system, immune
system and endocrine system, the three systems mutually supportive
cooperation. Hormones which is part of endocrine system are formed
and released into the bloodstream by various glands including the
gland testis, ovary, pancreas, adrenal, thyroid, parathyroid, thymus
and pituitary gland. Hormones are very essential to the operation of a
number of biological processes the body, which act as messengers
between cells or organs. For example, the hormone estrogen,
progesterone and testosterone, its play an important role for the
growth of reproductive organs, thyroid hormone plays an important
role in the growth of the brain, and the insulin hormone in regulating
the amount of sugar in the blood. Hormones work as a messenger for
the gene in the cell body. If the hormone system working properly then
the message will be brought right. But if anyone disrupt the hormone
system, the message it carries can be wrong, or even carry his
message. Each hormone must bind to work with the special receptor
protein. Specific receptors of each type of hormone is different
between the hormone with each other, such as the lock and the key.
After binding, the hormone can work to bring the message to the genes
in the cell body. Some industrial chemicals can work as a disruptors of
hormone system (hormone disruptors). It mechanism itself is variety,
some are involved in the interaction with the receptor, some involved
in the production or elimination or reduction of hormones and
receptors,

all of which affect the message hormones needed to

produce normal growth.

As for how hormone disruptors interfere with the hormone system:
1. Like hormone so it can properly bind to hormone receptors, for

example; xenoestrogen like hormone estradiol that interfere with the

hormone estrogen plays a role in reproductive function
2. Stimulating hormone receptors that increase the number of
messages over normal value.
3. Inhibit hormone binding to its receptor, which these obstacles can be
weaker or stronger than the original hormone that can increase or
decrease the effect of the gene in the cell, for example; dioxins in
certain conditions, can inhibit the action of estrogen and anti-estrogen,
rats affected by substance blackened vinclozilin, fungal insecticides,
have off spring without male reproductive.
4. Eliminating hormones by stimulating the destruction or removal of
hormone
5. Interfere with the activity of enzymes that affect the removal of
hormones so that the amount of hormones to many of the normal
6. Damaging hormones directly or indirectly to the structure or the
process of its formation

II.2.2 The Effects of Endocrine Disruptors

Since hormones play as an important role in shaping the normal
growth, disruption of hormones by the hormone disruptor system can
cause permanent damage. A very small amount of hormone disruptors,
can cause a large permanent changes. There are some that are
bioaccumulative which accumulate within living body without being
able to be excreted.
Effect of hormone system disruption invisible and only visible in a long
time, as example:

Changes in behavior as a result of changes in neurological response

and intelligence
Reproductive Tract abnormal, movement and decreased sperm
count

Balance the hormonal system is messed up

Lowered immune function
Tumors in reproductive tissues.

Effect of hormone disruptors on embryos level can cause permanent

changes and invisible. Hormone disruptors does not affect the mother,
but the effect will be seen by the offspring after puberty, for example:
1. DES (dietistilbestrol), a synthetic estrogen that is used as a
preventive medicine autumn womb may increase the possibility
of outbreak of vaginal cancer, uterine deformation, abnormal
pregnancy and immune system problems in the offspring, the
mother was not at all affected by the DES.
2. Dioxins are given on animal pregnant mice, it produced offspring
with

abnormal

reproductive

system,

such

as

smaller

reproductive organs, reduced sperm count and behavior more

than ke'jantanan'nya ke'betina'an.
3. PCBs (polychlorinated biphenyls) decreases the amount of
progesterone, a hormone of pregnancy guards, with the
accelerating destruction progestrogen hormone in the liver,
resulting in miscarriage easier.
4. The reduced movement and sperm count as a result of PCB by
increasing the amount of estrogen or anti-androgen on the
growth of the baby / fetus or newborn

Many studies have shown adverse effects of hormone disruptors

in the life of wildlife, for example:
the death of a large number of seals in the North Sea in
1989, seals in the Baltic Sea in 1992, the dolphins along
the west coast of the USA in 1989, striped dolphins in the
Mediterranean Sea in 1994, showing the influence of
synthetic chemicals and heavy metals which lowers the
immune animals and increases the likelihood of contracting
the infection.
Blood sampling in animals in florida panther males shows a
comparison of the number of abnormal steroid hormones,
as a result of estrogenic pesticides in the western USA.

 Serious feminization of hormonal damage in animals

crocodiles in the lake Apopka, Florida as a result of the use
of a type of pesticide DDT, which has grown alligator
production of estrogen and testosterone a bit, and the size
of the testes shrink a half to a third.
Beluga whales in Quebec have two male and female
genitals
Because humans at the cellular level / phones have in
common with animals, it is not unlikely that something
happens to the animals, it will happen to humans,
according to the opinion of an expert Dr. Lou Guillette.
Therefore, the damage humans do to animals, is indirect
damage to the man himself.

II.2.3 Methods of Reduction Endocrine Disruptors

The base problems causing substances Hormone disruptors is
the industrialization that swept the world. Parties deny industry is as
the cause, saying only to meet consumer demand, and still continue to
produce

and

use

hazardous

chemicals.

Being

in

the

field

of

agribusiness, pesticide use can not be avoided, also in order to meet

the needs of human needs. Therefore people as consumers should
reduce their need, for reduction the use of harmful chemicals and so
then the industry will also looking for alternative ways of safe
production. Avoiding the use of synthetic chemical pesticides or
pesticide replace it with organic. Avoid the use of plastic PVC (poly
vinyl chloride), drycleaners that use chlorinated solvents and other
products or services which release dioxins and other toxins into the
environment remain. Start getting used stuff reuse, refill, refuse and
recycle.
The government and industry must continue to try to create a
policy that encourages the creation of a safe environment from
chemical substances contamination. Conduct research has been done

on an ongoing basis in connection with industrial waste materials

discharged

into

the

environment.

Make

screening

to

identify

substances that are hormone disruptors, provides education for

product information to the consumers about the dangers, how to apply
cleaner production and pollution prevention.
How to cope with contaminated substance of hormone disruptors
are to apply eco-design and clean-production, is the design of products
and processes using a minimum of energy and renewable natural
resource

and minimize risks to humans and the environment.

For

example, the construction of homes that use solar energy, clothing and
food ingredients derived from organic materials, etc.

II.2.4 Substances Known and Suspected as Endocrine

Disruptors
1. Organo-halogen: Dioxins and furans, PCBs (polychlorinated
biphenyls),

PBB

(polybrominated

biphenyls),

octachlorostyrene, hexachlorobenzene, pentachlorophenol

2. Pesticides: DDT, DDT metabolites, dicofol, dieldrine,
endosulphane, lindane, heptachlor, kepone, malathion,
methoxychlor, metiram,

nitrophen,

ziram, Penta

until

Nonyl-phenol, bisphenol A, phtalate, styrene dimer and

trimer, Benzo (a) pyrene
3. Heavy metals: Cadmium, Mercury a polluted substance
which have a wide spread and binds to hormone receptors,
that are suspected of having influences disrupt the
reproductive and hormonal systems: 2,4-dichlorophenol,
diethylhexyl adipate, benzophenone, N-butyl benzene
II.3 Effect of Endocrine Disruptor (EDC) on Thyroid Function
A large number of chemicals that come from industry known to
cause a decrease in the amount of thyroid hormone levels in the blood.
According to Howdeshell more than 150 kinds of chemicals, both from
a variety of mechanisms are said to lower serum thyroid hormones.

The first stage in the synthesis of thyroid hormone is the uptake

of iodide into thyrocyte by sodium or sodium iodine or iodine symporter
(NIS). Iodine is an essential thing for the synthesis of thyroid hormone
and iodine deficiency is a significant problem at this time. So when the
NIS obtained a disturbance can interfere with thyroid hormone
synthesis or from can cause iodine deficiency. Examples of existing
chemicals is perchlorate, thiocyanate, and nitrate.

Iodide is a form of iodine that enters the cell, it first had to

undergo

oxidation

to

form

higher

oxidation

before

being

transferred to the thyroid hormone precursor thyroglobulin. A

biological substance known as an oxidant

of idodide is H2O2,

and O2. Formation of iodine itself is controlled by the enzyme

thyroperoxidase (TPO), which is a heme-containing enzyme. And
some of these chemicals are known to inhibit TPO, one of which
is 6 - propyl-2-thiourasil, (PTU). PTU is known as a material that
lowers levels of T4 and T3, and to increase levels of TSH in the
circulation. Other substances that can inhibit TPO is isflavon,
specifically found in vegetable protein.

II.4 Physiology and Thyroid Receptor

Hormones secreted active thyroid gland 93 percent of them in
the form of thyroxine and 7 percent in the form of triiodothyronine.
Even a percentage far more thyroxine thyroxine but all this will be
changed to peripheral tissues triiiodothyronine. Triiodothyronin 4 x
more potent than thyroxine, even its blood levels is in much less of
time and much less in the blood.
Thyrotroph cells covers about 5% of the cells of the anterior
pituitary function and are located mainly in the anterior gland. They
are smaller than other types of cells with nuclei and irregularly shaped
flat and relatively small secretory granules ranging from 120-150 m.
In the early stages of thyroid hormone formation, a process that
occurs is iodide transport from the blood into the cells and follicular
thyroid glandular. This is called iodide trapping. The next stage is the
change that occurred previously experienced iodide transport into
thyroid cells, the changes in the form of iodide oxidation itself. Iodide
undergo deoxygenation would eventually attaches to thyroglobulin in
which this process is called organification of thyroglobulin.

During the process of deiodionisation, the work is done by

a peroxidase enzyme and a peroxidase enzyme works in
conjunction with hydrogen peroxide. This enzyme has an
important role, so if there is a blockade of the enzymes or a
condition that causes the peroxidase is no good with the acquired
or congenital, the production of thyroid hormones can be very
low or even no production at all (Guyton , 2006)

Picture: the formation of thyroid hormone

TSH is a heterodimers glycoprotein hormone composed of two
subunits relationships and noncovalent. This subunit common to TSH,
LH, FSH, and hCG, but the unique subunit and determine its
mechanism of action. Subunit transcription is inhibited by T3 in the
region close to the transcription initiation site. 4.9 kb-TSH subunit gene
is located on chromosome 1 consists of three exons and two introns.
Pit-1 binds directly to the promoter of genes to give expression to
specific

tissues.]

TSH-suppressed

gene

transcription

by

thyroid

hormone receptor directly in exon

Production of mature heterodimeric TSH molecule requires

cotranslational
translation

glycosylation

and

and

decomposition

subunit

complexes.

signal

peptide

After

subunit,

glycosylation occurs at asparagine 23 in subunit and the two

asparagine residues, 52 and 78, the sub-unit. TRH and TSH T3
regulate glycosylation, although in the opposite direction. Giving
TRH or T3 deficiency, such as occurs in hypothyroidism or T3
resisitensi, increasing the addition of oligosaccharides on the TSH
molecule (Larsen et al, 2008). Since the feedback control of TSH
secretion by peripheral thyroid hormones are very sensitive,
most thyrotroph disorders can be diagnosed by measuring basal
TSH and thyroid hormone levels. However, the dynamic TSH
measurements may be needed to fully assess the integrity of the

axis hypothalamus-pituitary-thyroid. TRH (200 to 500 mg) was

given intravenously, and TSH levels were measured at -15, 0, 15,
30, 60, and 120 minutes. In euthyroid subjects, peak TSH levels
(up to 22-fold higher than basal) was observed after 30 minutes.
Because of the feedback suppression of TSH by thyroid hormone
levels

high

positive

signals

override

the

hypothalamus,

hyperthyroid subjects had undetectable basal TSH levels that do

not respond to TRH. In people with primary thyroid failure, the
response of TSH is very high, but in those with secondary thyroid
failure associated with pituitary disease, TSH levels did not
change in response to TRH. TRH infusion up to 4 hours of
continuous

improvement

in

TSH

menunjukkanl

biphasic,

reflecting the initial release of TSH long-synthesized, followed by

a newly synthesized hormone. Prolonged infusion of TRH further
increase the levels of thyroid hormones, which suppress the
synthesis

and

release

of

TSH.

Within

few

hours

of

administration of T3, basal TSH levels and TRH-evoke suppressed

TSH levels decreased. T3 suppress hypothalamic TRH synthesis
and decrease the number of pituitary TRH receptors, thus further
limiting the biosynthesis of TSH. The stimulation and disruption
of the endocrine vandals and substance, this can affect the
amount of TSH itself and TSH receptor.