Toxicology

Lecture 1 Introduction to :
Toxicology ·
Evaluating the Dose-Response Relationship
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toxicology-study of the adverse (boxic) effects of chemical & physical agents living systems under specific condition of exposure on

integrates knowledge techniques from biochemistry biology chemistry genetics medicine Pharmacology physiology physics & applies salety evaluation I risk assessment to the discipline
v , , , , , , ,

-
scope of boxicology : Omedicinal industry Hood additives) griculture (pesticides) industrial Isolvent dyo) Ranimal toxins
Plant

.
,

*
History of toxicology been exceeded
-

hemlock metal Kopper head

" of the oldest
one
writings contain information which ruler to many recognized prisons , um
,

& rates of the victims of hemlock

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one
t appears
*
Paracelsus-father of
Loxicology substancespoisons there are ; is none which is not a prison .

night dose differentiates

The a poison & a
remedy
↑
-

* Classification of Toxic Agents ↑ toxid

(LLDSO =

s animal Rplant on a
additive anar, liverinju
elect
term of their D target organs I liver Kidney,)
stabuse Incide t
-
in ,

lig/ng/body wt) causing

-

the desage
(nonobservable a
dr
③ ithcalstate Danical ②
poisoning potential
exposed animals
-
death in 50 % of

toxicity lethality
· depending on their nature as : O toxin-toxic substances that are produced by biological systems such as plants animale Lungi backina
, , ,

gives
measures

a
acute
-

measure of the
or

immediatoracute boxicity of chemicala

uskevenom/botulinumboxin / Zeralenone IZEN) produced by mold a in the strain , sex -

Rage gop of a particular inimal species being tested

② toxicant-it rebers to toxic substances that are produced by-product by or a of human activities
Dioxin [12 3 7 8-tetrachlorodibenzo-p-dioxin (TCDD)]
Be , , ,
-

· Characteristics of Exposure
- toxic effect in biological system depends on: used to indicate the does that cause advese
the rate at which injury builds up used to indicate the effectiveness toxic effectsSother than death
target site & the duration o
① the concentration at which the substance reaches the
-
this exposure
f =>
steeper curve-bigger slope buxicity of a substance
Co
=

-
⑳ the chemical R physical properties of agent chemical properties of th 'nontoxic &
Physical
3
: is
agents ; causes skin noral, ,
Blung ancer
ITD
Dinorganic mercury -
> XcrnBBB
ironic mercury - cross BBB CED)

② the are situation >

- how the
agent is metabolized by the system & the overall
surreptibility of the biological system subject or
I

-- of
① roube & site of exposure ③ duration & frequency exposure
·

· toxic agentsOaccess to the body are leaseroutes

major routes by which goin extto gain access --
I dose may give
box effects if X

4
GIT lingestionI lungs (inhalation) shin Itopical otherparenteral cubes Duration given at several
diff .
Lines
frequency
&
, , , ,

quency exposure Relimination

etwas he rate
>
-

is of
produc the grabet effect most vapid response when introduced
a
toxicagentsgenerally
·
-
- - fractionation of the total dose alone will not solve
· -

half life must be considered

approximate descending effectiveness for the
order of routes
= >

toxicity so climation
oral Application of DRC
7 an are
·
intraperitoneal #
mechanism of
boxicity differin forme oftoxicity
intravenous inhalation
-
> intramusculars dermal

Land -
in acube toxicity CNS depression
>
-
- ( T
Efficacy
-

in chronic
toxicity - liver cirhosis TherapeuticIndex (TI) Margin of Safety ↑ exposure (MOS) Potency
= of doses over which a chemicalproduces maximal officacy reflects the limit
rabio between thedoe required to produce boxicity ratio between the dese that is just within the boxic range
the dese the desired therapeutic increasing responses
required to produce range to 1 % of population & the doe that's 99
% of the dose-responsei s on the response ax is

response [ potent * to a certain chemical

effective to the earlier on x-axis)
population
-

TI = ↑ potent earlier on Y-axis)

24 officient J =

Spectrum of
· undesired effect (boxic response intoxication)
offet adverse deletions x effects
(underedeffect site , , , ,

[TI
Mos =49 · Toficient
dry/boxient]
-

-
= ↑ sale
chin to see
info [↑ MOS ↑ safe drug/boxicant]
ourattest Letcontactlimitationof,inhalation
=

I
immediate rapidly offer single administration of substance ·
occur
-

a
-
welling fise-
of

vs-delayed-occur other a
lapse of some time motiinogeniceffect of chemicals systemic-require
site
tuxicant hom it entry point to
absorption & distribution of a distant

- Phenomena where substance is beneficial of low deve But Causer advers effects at higher des

·
achy ladproducts consin of
actionistansportedly hapof lo now minimum daily requirement ,
as well as the
e ae
- -

the threshold for salety may be associated withD toxic effects

adverse v t chemical
depende on
organ's ability S
to generate ,

alleic
raction-immunologicalmedily ated resulting previou
4 Us eversiblecase oflivera
-

in S focuses on Lindividual
>
-
A
a
A
-

idiosyncratic reactions (genetically determined abnormal activity to a chemical L) interaction of chemicals The deve range that
results in tit
effect-when lined effect of
I chemicals is to the sum of the effects of each given alone
-
deficiency toxicity
Digh ① additive
nor
* Do
response either extreme sensitive to dose or extreme insensitive to der a equal = -

&
-

(2 + 3 5)
t in curtain
=

due to
enzymes 2 chemicals
⑤ synergistic effect when combined effect of are
greater than the sum of the effects of each
-

I that has & in

chananmenrynrachchan
-
grp of pp deficiency 19 + 2 18) =
agent in alone

nitrite
e
methemoglobin ③ potentiation-one substance ha boxic effects but when added to another substance if

I
I
like
preparation
-
10 + 2 10)
=>
S
makes that substance more toxic
=

isopropand thepatotoxic
is , but when with betrachloride it & *
given Ebon hepatotoxicity
⑭ antagonism-when I chemicals together interfere with each other's actions or one interferes · Variation intoxic response
with the action of another
(+
4 +

---
·

=>
antagonistic effects of chemicals are often very desirable Toxicology
in
zars of antidotes
- barbiturate intoxication can be
antagonized effectively by IV administration of NE

Dose-Response Curve (DRC) graphical representation

ollect
of the quantitative is between doses of a substance

specific
boxic
① -
*
-
-
-

individual dose-response relationship quanbal done-response relationship

-
individual organism chemical characterizes the distribution of responses to different doses in population
- - -

varying doe of
<
-describes the response of an to a
a
-

of individual organisms
①graded " response tem
continuous
a
it's
-

over a
large

&
Bell shaped sigmoid curve
the Luquency of all-or-none response to the boxic anyed within a population is plotted
o,
grad

timsaleat
all-or-none effect labe ordead with a laiture or without
·measu
-
,

> used to predict what proportion of population will respond to given dose of
a a

boxicant
a is
population studies
·
to plotManballs we must fibrate the population with increasing doses
untyvirtually response
pequency of effect
to dese

importance of DRC
*
studying
D iMC is considered as the cramtitative of
toxic response

② to limit the exposure levele doses to which

any
individual or living organism in Community might receive that produce a serious adverse effect
-

③ helps the environmentalists to develop of regulationz rules that could control the chemicals harards
community or public practioners , a
policy
 it to determine the possible rishe associated with expose
the quantifyinggatheringprobability
all available information the toxic effect of agent evaluating
Lecture 2 Rish Assessment process of
Objectives of Risk assessment
an e
:
> on
-
the of harmful effect to individual or populations from exposure to specific amount of hazards

⑧balaalutant
-

Areas of
·
Toxicology l acturer enment/enumer
organizationa
① Mechanistic
boxicology-identity the cellular himical & molecularchanisms by which chemical exerts its
, boxic effects on
living organisms ⑭ estimate residual risks R extent of risk reduction offer steps are baken to reduce riske
voity
indiv
allows mechanisticLoxicologist
Toxicogenomic protect genetically susceptible Daustomise hey they based on their individual genetic ma
a
-
-

② Descriptive toxicology-concerned directly with toxicity testing which provides information for salety evaluation & regulatory requirements
③ Regulatory
toxicology-it's concerned with the use provided by descriptive mechanistic toxicologists for the use of chemical in real world
of available data a

Toxicologists involved in the establishment of standards for hunts of chem cals permitted in ambient air industrial atmosphere &
reg
.
are
drinking water
,

Ga
* Risk assessment -

> a term used to describe the overall

process or method where you :
Didentily hazards & risk factors that have the potential to cause harm (hazard identification)
② analyze & evaluate the risk associated with that hazard list analysis & risk evaluation
③ determine appropriate ways toeliminate the hazard ,
or control the risk when the hazard can't be eliminated lisk control

based(
* Risk Assessment Process know order)
iscience

[1 HazardIdentification Itoxicity studies 2 Hazard evaluation Dose-Response Assessment

Exposureterment timperie od?)
or El Risk Characterization
Twhat health problems by the pollutant ?] [what .I How much of the pollutant many pplav exposed ? What is exposed population.
·

are caused are the health problems at different exposures how the extra risk of health problems in te

collecting data from different sources to determine whether a substance is tuxic or not :
-performed if the hazard identification process produces evidence of a hazard process measuring the magnitude frequency Eduration&
of estimating or ,
of exposure to agent
along with thean ,
s
puts all the information gathered from all other steps together to determine the
* characteristics of the population exposed describes the sources
data fom Loxicological epemiologicalste a ->
pathways Routes in the assessment
Wolvesgathing
_
Gaming Iname) -the purpose is to calculate the dose at which a harmful effect willoccur
-
, actual risk of exposure to a specific boxic substance

ourpomelordth)
factor to consider when
boxicologiswt hat
explosive
performing an exposure ann
a

pos
le
-

... the dose response assessment bulle the n - l e t h a l done 50

①generainl toforrachchechemcppemaCormulasbucture
,
· ,
a
, ho
-

② LOAEL lowest derived adverse effect bur

-

city information -

studies ③ exposure pathways environmental late transport & transformation

D
boxicological
-

- -

S - ⑨ exposed human population-size characteristice location hab if

IDSO , ,

berting
,
acute boxicity
toxicitytesting
-

chronic
-

⑤ measured or estimated concentration best to obtainsamples from

-

source of exposure to calculate amnt of

boxic substances present
over along periode a or
through mathematical model

morethe
administeredover*
compoundis cly
- -
·
inmalspiele for
days -
threehold approach non threshold approach
-used for
majority of non-carcinogenic ·
*
used for cancer and point when there is not a dose
factorsaffecting ampds
*
toxicological besting :
from O to limite bwhich dow x measuralsle effect in the organism
there is&
has
range of exposures
·

Species of test animal to the agent--abvase response

-

① that can
value -blerated by the organism any exposure
the exposure of particular individuals orpopulations
⑤ measurement of exposure-to
quartily
with essentially①chance of expression of St
offecting toxicity lage
② variable
of ofpopulation)
study
:
- , sex, health a subs -
⑮-
which depends on route exposure
, on direct approach Indirect approach
diet , lifestyle choices occupation n. by monitoring the pollutant concs reaching the repondents various locations
during specific
③ , > , measures ones in or

② epidemiologie
st -
-

Chandliner bloty
-
, sample spltblood
, samples humanactifiesHukomaino
predict
ea

environmentalwater air, ,

* split sampling-bechnique whereple samples collected from the same

are location at the same
time I
-
*
sant to d to a t
if they get similar
see result

Risk Policy based

*
Management
-
-

·
 insulin produced but it doesn't do its joh)
Lecture 3 Toxic Effects of Calories
:
** Insulin Resistance (there's
hormonal the endocine cells of the t ime ladipolines
pantere at (gut neuropeptides critical the multiple proces
-
messages generated by -
,
tract are to
orchestrating
& Nutrients associated with Lud thux metabolism D
D state /direct storage of nutrients in form of glyogen ,TG & proteinI
both-led
* xs

A
= - -

embolichormone) lasted stateTolucagon

*
, insulin the principal hormone levels in * storedfland
-

required to manage nutrient

-
stored blood the movement of nutrients into

--
-

-
=>
glucose metabolism is controlled big crein adipo
muscle alle by imulin xhibition
of
glucose production in liver serving as the
buy regulator of bloodglasse concentration
-

a inability of insulin to promote normal glucose upbake by lat & muscle inhibit hepatic glucos production nulin
resistance (IR)
&mina
e
,

-
①
Chronic key feature o
/th is
type diabetes
a f I , Cancer ,
- - obesity
-ganic impganic -

erglycemia
resultinghumsysteminulin a hyperinsulinemia Soma
resistano compensatory insulin scretion & in

- insulin cover
weightgain where the celle absorb too much ge
A he
body converts them to let

I Shahomaenergyin lovingoganim ele resume of preset as

#
-

·staminat hi
-
gene

Metabolism A =
· Energy Expenditure
· -

breaks molecules to produce

③
energy
#
-

* a pason's metabolic rate determinant of energy expenditure -

Lobal energy consumed
When =
total
energy required to meet
hosal metabolic needs relatively table weight healthy body composition
3
Metabolic rate is expressedar Basal metabolic rate (BMR) the amount of person d
energy expressed
in calories that
⑮
· -

& to keep the body functioning of rish

point" hypother's - intake
coordinately regulated by delined regions in the CN mothalamue that signat to
energy expenditure are

constant level of energy body weight

⑭ninupthtetlanthe
e maintain relatively
a & reserve
②
u adipose bissue is highly innervated
by sympathetic NS &
advenegic stimulation whichactivates lipolysis in lat Cells &↑ energy expenditure in
-
-
amount
type , Ihr other me adipose biseue & skeletal musce
*
max
-
--

I &
the hormone leptin the Let -
identified or homeostatic regulator of
signal to be
energy
balance

budintaty
-

require energy to genuate macromolecules acts on

metabolic-censing neurons in brain receptor-mediatedactions - >
pulating signaling pathways homore
secreted in proportion to body lat stores from adipose bissue in which havingAobesity results in hyperleptinemia
obsse ppl to *
appear be resistant to the - satiety effect of leptin

TG begin to accumulate in non-adipose

Biology of Obesity lobesity related to excess Gloric intake/obesity
risk)
o *
⑰
Toxicity non-esteified bisseves like liver sheletal muscl , Pancreas
,

as lipid droplets
fatty acids
① several most of these
genes-whose disruption causes severe monogenic forms of familial obesity
genes impair central control Good intake
of

↑
>
-

bosis of
but , the
genetic non-syndromic (common) obesity has remainedduive ⑤ &
>
-
monogenic obesity-rare severe early-onset obesity with abnormal feeding behavior & end disorders
-
ne (mainly due to autosomal recessive mutations in&
genes
>
of the
-
lybin-melanocortin B -
-

matemptio
pathway which plays they role in the hypothalamic control of Goodintake -
-

A
-

-
-

Epigene D- -
-

getational weight
n a
-

*
-

Types of Obesity =
- -

w
&
-

& E
this leads to of new adipocyte
-formation a cluster of metabolic abnormalities associated with the
a
Hugh development of Cardiovascular disease type I diabetes
-

lasia 2

*
which is mainly due to central
obesity
·

*
Alternation in Pharmacokinetics & metabolism in Obesity ⑮a
D
,
Endocrine dysfunction in Obesity
Obesity & Cancer risk
determines
A
>
-
hyper insulinemia has by effects endocrine system
on :
= TBMI is associated withI
= > -
cancers risk >
- Could be related to endocrine & metabolic disturbances associated
with obesity in which :
volume of distribution- I growth hormone (GH)&
secretion is dramatically suppressed in both adults & children due to
insulin &IGF-1 receptors be late activation
1 -balls througheach other's all protituation
-

- vio
- -
- -
-

of MAP-kinase Cascades
direct feedback effects indirect effects
⑤
-

D ② D
to thepituitary &
of insuti deduction insertion
- increased sex strvoid concentrations & atipokines promote growth tumes in the
obesity endometrium
suppression of IGF-binding protins ummary gland
results
-

a in , ,

& take of obesity-associated cancers

-
-

#
-

be obese ppI have of endnewGH-releasing peptide n that's

larger lat
be I
a which lead to in

· entiich
distribute
*
-
-
-
produced by stomach & hypothalamic centers
- -
Can exert a -vebeedback on GH secretion
=
15) increased leptin is proliferative antiapoptotic
langiogenessuppress
,

adiponection
,
2
ton of cellular antioxidant
on
proinflammatory -rotes new blood vessel formation

-
in reas auction
adrenal androgen .
Aplasma concentration of sex hormone-binding globulin (SHBG)

ranhrogipheral gempoyyoaysyndmine
-

a
leadih
ng
>
-

be
-
they don't partition into lat - - & - g
E -

= -

-
=

A
-

-
-

D
Toxic effects of dieting Drug therapy for weightloss
BMI of 27kg/m2 or greater with other besity related risk factors
① if diet doesn't include all the required nutrients limbalancedI metabolism will suffer & with time this
,
can result in health problems pharmacotherapy should be reserved for patients with BMI of 30kg/m2 or
greater or a

druge classified according to their MOA :

delici paintentcouldhad
>
-

s-
altho metallingenzymes
a i Suppression of appetite suppression of lat absorption Orlistat
② Yo-Yo effect weight cycling --
-

or

oily stools o spotting

latty or ity abdominal pain Natulence soft stook,
Sibutramine /Meridia
, , , ,

Sympathomimetic diethylpropion
- - -

o
Hauser

blongtermuslad like amhymiadam,daysa

-

withdrawn from market since 2010 due

Go
⑫i attacke Stoke
=>

reduce absorption of lat soluble vitamin

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Q ailability o vitamine
⑫
Surgical intervention
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long function tests for studying Lung Injury (Pulmonary function Studies
- include measurement of UC TLC
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functional residual volume TV airway
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resistance, maximum How ,
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①
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·
 Lecture 10 ReproductiveToxicology I
:
·
examples of drugs which interfere with hormonal Control of gametogenesis
S Because of the process of reproduction is under the hormonal control therefore; interference with the secretion of hormones such as GnRF, LH, FSH, testesterone,
estrogens, or progestins could have an impact on the reproductive ability.
the function of reproductive
system complex & involve many relatively unique
are cellular level response
examples
- chemicals affect reproduction in males females
can adversely
1. Reserpine ( antipsychotic, and antihypertensive drug),
-

> Recent trends in human fertility point shows decline in normal human 2. Chlorpromazine (used to treat certain mental/mood disorders such as schizophrenia
reproduction and suggest that exposure to environmental chemicals and 3. Selegiline monoamine oxidase inhibitors (used as a treatment for major depressive disorder and Parkinson's disease)
drugs may contribute to these declines.
-
- The previously mentioned drugs modify the content or actions of brain monoamines that affect gonadotropins.
N.B: the neuroendocrine neurons have nerve terminals that contain
3
In fact, infertility is an emerging global public health issue 8
after cancer and =
monoamines (norepinephrine, dopamine, serotonin), that impinge on them.
cardiovascular diseases, thus illustrating the necessity of identifying the
-

causes of infertility. 4. GnRH analogs [e.g., Buserelin (used for -treatment of prostate cancer and endometriosis )] can interfere with both ovarian and testicular function.
-
- Buserelin side effect: with chronic administration of buserelin the GnRH receptor becomes desensitized and completely stops responding to both buserelin and
- -

endogenous GnRH.
-
-

- This is because GnRH is normally released from the hypothalamus in pulses, which keeps the GnRH receptor sensitive; whereas chronic buserelin administration
·
frequencies of selected reproductive failures results in more-constant exposure and desensitization of the receptor.
-

- -
·

in males in females
5.Estrogen and progestin: block spermatogenesis by suppressing LH and FSH 7.Anesthetics and analgesics that interfere with either neuronal or
and thus - -
suppressing testosterone secretion. hormonal control of hypothalamic or pituitary function can * prevent-

6. Anabolic steroids ( they are synthetic drugs that were developed in an ovulation.
⑮ -

attempt to separate the anabolic (muscle building) effects of steroids from the 8. Birth control drugs such as oral contraceptives as well as injectable (
androgenic Depo-provera) and implantable (Norplant) act on the hormonal
(reproductive effects), however, this separation in fact is un-achievable since system.
-
both reproductive -
and muscle -
tissues seems to contain the identical type of
-
• These drugs contain a mixture of estrogen and progestins that

·
·
androgen receptor (AR).
-
inhibit the release of FSH and LH and thus inhibit ovulation.
• Anabolic steroids has negative feedback on hypothalamus and thus side • Side effect of theses drugs include: some increase in risk of
effect of theses synthetic steroids include lowering testosterone level and thromboembolism, mycordial infarction and stroke.
* *
S suppress spermatogenesis ,in addition to, hepatotoxicity, behavioral • These risk increase with age and with the presence of contributing
-Definitions changes andS potential shortening of stature males through premature factors such as smoking and cardiovascular disease.
-

reproductive toxicity includes thetoxic effects of a substance on termination of long bone growth.
-

- --
=

⑤
ReproductiveToxicity
/
*
Developmental Toxicity
defined by the Globally Harmonized System
-
means adverse effects induced during
pregnancy, or as a result of parental
Male reproductive
tissues & besticular function
as adverse effects of chemicals on sexual
the process of spermatogenesis
function and fertility in adult males and
·

*
exposure, manifested at any point in the -
· can be broken up into several distinct
stages each corresponding to particular type of Cells
, a :

females, as well as developmental toxicity in life span of the organism

the offspring
-
--
leydig Cells
-

Serboli Cells
The
gonads (bestes ovaries) have Dalfunction
a

• Normal spermatogenesis requires Sertoli cells. • Are the primary site of testosterone synthesis.
-- • *
LH stimulates-testicular Steroidgenesis; i.e.: synthesis and secretion of
*
endocrine function *
endocrine function
non
•
·
N.B: Spermatogenesis: Formation of mature sperms
Serboli Cell functions
-

male sex hormones (testicular androgens).

involve the production of germ
involving the secretion of&hormones in which the
sex
-
cells (gametogenesis).
1. Plays an important role in Spermatogenesis ( under the influence of • S
Androgen are essential to spermatogenesis, epididymal sperm
- -

maturation, the growth and secretory activity of accessory sex organs,

sertoli cells the# spermatides separate and mature into the
·
Testes secrete male sex steroids including -
-

&- -

somatic masculinization, male behavior and various metabolic

Dtestosterone(TS), dihydrotestosterone (DHT) Aspermatozoons).
Spermatogenesis oogenesis
-

and small amount of estrogen

-
processes.
=

-
2. In early fetal life , they secrete antimullerian hormone (AMH); thus -

preventing differentiation of the& female internal sex organs in the male

⑮
Ovaries depending on the phase of the menstrual · examples of chemicals/drugs causing bydig cells hyperplasia/ neoplasia in rodents
- -

cycle, secrete various amounts of estrogens and fetus. -

progesterone. 3. After puberty, these cells secrete the hormone inhibin, which may aid in
-

- =

modulating pituitary FSH.

-

4. They provide germ cells with nutrients, structural support as well as

S
Gametogenesis ( Spermatogenesis and Oogenesis): the process in which cells undergoes meiosis to * -
-

secrete regulatory factors androgen-binding protein (ABP) which acts as

produce mature gametes.
-

- -
carrier for TS and DHT.
D Gametes: a mature haploid male (Sperm) or female germ cell (Egg) which is able to unite with. 5. Sertoli cells together with tight junctions represent one of the most
-
-
-

another of the opposite sex in sexual reproduction to form a zygote.

= -

important protective mechanisms in the male reproductive organ known

& Germ cell: a cell containing half the number of chromosomes of a somatic cell and able to unite
as*blood testis barrier. This prevents the free exchange of chemicals/
with one from the opposite sex to* form a new individual; a gamete. -

drugs between the blood and fluid inside the seminiferous tubules.
-

N.B: Through out the process of gametogenesis there are several points at which toxicants such as
*
alkylating agents may act.
- effect of toxicants on make reproductivedisue
• Many compounds and chemicals that affect spermatogenesis act on the
*Sertoli cells which include:
1. Bisphenol A (BPA): is an industrial chemical that has been used to make
Hormonal Control of
Gamebogenesis
- Gametogenic and secretory functions of the ovary and the
certain plastics and resins since the 1960s.
• N.B Seeking out BPA-free products is not always easy to do as some
testes are dependent on: the secretion of manufacturers label their products as BPA-free which is not the actual · Posttesticular function
follicle stimulating hormone (FSH) and luteinizing hormone case.
Burlin • The end product of testicular gametogenesis is immature sperm.
(LH) from the pituitary. • If a product isn’t labeled, keep in mind that most aluminum cans or bottles
reserpine = Y
• Posttesticular processes involve& ducts that move maturing sperm from the
FSH and LH are glycoproteins that are synthesized and Chlorpromazin
- have linings that contain BPA, while steel bottles or cans don’t.
testis to storage sites where the sperm await ejaculation.
,

released from the* pituitary gland. selegiline 2. Pesticides as dibromochloropropane (DBCP): cause inhibition of -

• Erection and Ejaculation processes are * controlled by the central nervous

-
Hypothalamic neuroendocrine neurons secrete specific spermatogenesis; where its mechanism of action may be through= inhibition of
matea
semals
30 birth conled daige
= -
system (CNS) and& modulated by the autonomic nervous system.
releasingDgonadotropin- releasing hormone (GnRH) or anabolic progestiv
, oxidative phosphorylation.
hormones • Example:* Pesticides, particularly the organophosphates, are known to affect the

>
⑤
release inhibiting factors that act on anterior pituitary , where 3.Phthalates (plasticizing compounds) : may affect energy metabolism as
sirgenesis
they act to stimulate or inhibit the release of the anterior
-
well.
neuroendocrine processes involved in erection and ejaculation.

pituitary hormones which act on gonadotropic cells. 4.Cadmium: can cause testicular necrosis probably by decreasing blood flow
-

to the testes.
5.Lead: exposure to lead has been associated with infertility as well as
chromosomal damage in sperm.
Ellemal reproductive
tissues& Ovarian function 6. Tobacco smoke: can affect fertility in males where smokers have higher
• Oogenesis: About 400,000 follicles are present at birth in each human ovary. percentages of abnormal sperm than non-smoker.
• After birth, many undergo atresia, and those which survive are continuously reduced in number.
• -
Follicles remain in a primary follicle stage (primary oocyte) after birth and until puberty.
• At puberty; each month, one not yet fully developed oocyte (called a3
-
secondary oocyte) is released
from the ovary. This oocyte completes its last cell division when it is fertilized by a sperm.
-
-

· Ovarian
Cycle
• The cyclic release of pituitary gonadotropins involving the secretion of
ovarian progesterone and estrogen.
• These female sex steroids determine ovulation and prepare the female
accessory sex organs to receive the male sperm.

· effect of
toxicants on hemale reproductivetissues
1. Cytotoxic substances such as antineoplastic agents like ( 5-Fluorouracil, Cyclophosphomide and 6-Mercaptopurine).
-

2. Heavy metals.
-
3. Polycyclic aromatic hydrocarbons or radiation may damage oocytes and affect ovarian function.

elect such
deveday o development let me
which

agents
·

1. Partial destruction of primary oocyte : may lead not to immediate infertility, but to early onset of menopause as the total pool of primary
oocyte in the ovary falls below a minimum number.
2. &
Total destruction of primary oocytes: will lead to both infertility as well as to premature menopause.
-

3. Effect on mature secondary oocytes will lead to temporary infertility, with fertility being restored as new secondary oocyte develop.
· Many of the principles that govern the absorption, distribution, metabolism, and excretion of a chemical or drug also apply to the reproductive system.

·I
·
·
1. Testes: The mammalian gonad is capable of metabolizing foreign chemicals that have traversed the blood-testis 1. In males: Depending on the species, there are varying degrees of capacity of spermatogenic cells to
1. The maternal-fetal interface occurring at the placenta represents a barrier to chemicals coming in contact with barrier. Whether biotransformation occurs gonadally or extragonadally, the end result can be interference with repair DNA damage resulting from environmental toxicants.

lol
the developing embryo. spermatogenesis and/or steroidogenesis. • Example of Environmental toxicants which posse's an estrogenic activity include DDT and other
• N.B: the placenta is not so restrictive that it prevents most chemicals from crossing the placenta. • Examples: Amiodarone (antiarrhythmic drug) and its metabolite Desethylamiodarone, Acrylamide ( industrial use) and organochlorine pesticides and dioxin.
2. The male gonad has a somewhat specialized biological barrier the blood-testis barrier; unlike the female gonad. its metabolite N-Methylacrylamide, N-isopropylacrylamide.
2. In females: female gametes have an excision repair capacity unlike mature sperm, the mature oocyte
2. Ovary: like the testes, the ovary has the metabolic capability to bio-transform certain exogenous substrates. maintains a DNA repair ability.

p
• For example: Cytotoxic toxicants as polycyclic aromatic hydrocarbon (PAHs) is metabolized by cytochrome P450
in the ovary producing toxic metabolites which capable of destroying primary oocytes, which is one possible
explanation for the observation that exposure to cigarette smoke ( which contains PAHs) may lead to premature
menopause.
• Furthermore, the process of ovarian steroidogenesis is susceptible to different agents that interfere with the
biosynthesis of estrogens.
• N.B: Less is known about how chemicals or drugs interfere with ovarian metabolism. The ovary has not been
studied as extensively because of its more difficult and complex hormonal relationships.
·
• Difficulty in evaluating reproductive toxicity is related to:
To sum up we can say that targets of toxicant can be divided into:
1. The fact that a wide variety of chemicals and drugs can perturb the reproductive system.
1. Toxicant that can interfere with cell division such as alkylating agents and antimetabolites; in addition to physical
2. Not only the considerable diversity in the chemical configuration of toxicants but also the sites and mechanisms of action of toxicants can be very different.
↑
agents such as X- rays and other form of ionization radiations can cause decreases in spermatogenesis and
• However, several hormone assays are available to assess endocrine function.
I

oogenesis through effect on dividing cells.

• N.B: The endocrine system of the female is more complex and dynamic than that of the male. Hence, evaluating reproductive function in females is more difficult.
2. Toxicant exert their effect through direct action on cells of the reproductive system; example: Heavy metals,

↑
pesticides and chemotherapeutic agents.
I
I

3. Toxicant that interfere with hormonal control; example synthetic steroids ( anabolic steroids and oral contraceptives).
A

There are essentially two approaches to determine whether a chemical can exert an adverse effect on
spermatogenesis: • Reproductive endpoints that indicate dysfunction in the female include perinatal parameters as well as
1. Evaluation of testicular morphology. developmental toxicity endpoints.
1. In Male: 2. Functional evaluation of spermatogenesis. 1. Oogenesis/Folliculogenesis: several methods are used to assess directly the effects of test compounds
• It has been suggested that the human male is more vulnerable to environmental and occupational toxins than other • Included in the assessment are the detection of abnormalities in spermatogenesis, stage-dependent germ cell on oogenesis and/or folliculogenesis include histologic determination of oocytes and/or follicle number.
mammals. degeneration, and impairment of normal sperm release • Also; chemical effects on oogenesis can be measured indirectly: by determining the fertility of the
• It is worth mention that chronic illness may have a profound affect on gonadal function; systemic illnesses that offspring.
reduce spermatogenesis include thyrotoxicosis, hypothyroidism, renal failure, mumps, and Crohn's disease. These approaches could be determined through various tests which include:
• Follicular growth and kinetics may be assayed in experimental animals in which the sizes of follicles,
• Aging, nutritional deficiencies, and obesity also can affect fertility. 1. Invasive approach involve:
oocytes and nuclei were measured.
• N.B: Dietary deficiencies of manganese; vitamins A, B6, and E; and zinc are well known to cause spermatogenic I. Testicular biopsy: which can be used in selected circumstances to evaluate spermatogenesis.
• Examples: Azzospermia which can be caused by certain chemical agent, infections (e.g.: mumps) ,hormonal 2. Estrogens and their receptors :
arrest.
defect and genetic disorder ( e.g.: Klinefelter’s syndrome). • Estrogen influences the growth, differentiation, and functioning of several target organs which include
• N.B: Klinefelter's syndrome is characterized by testicular dysgenesis with male morphology and an XXY the mammary gland, the uterus, the vagina, the ovary, and several male reproductive system organs
2. In Female:
karyotype. In which, failure of the sex chromosomes of either parent to separate during gametogenesis is called (testes, prostate gland, etc.).
• Many physiologic, sociological, and psychological factors can affect the normality of the female reproductive system,
nondisjunction and can result in gonadal agenesis. • Estrogens exert its effect by an intranuclear binding protein called the estrogen receptor (ER). The
as evidenced by variations in the menstrual process.
II. Testicular histology: which provides information on target cell morphology. receptors for estrogen (and progesterone) are members of a large superfamily of nuclear proteins.
Di

• The factors known to affect menstruation that are for the most part unrelated to occupational settings include age,
• Serum levels of estrogen and estrogenic effects on target tissues are indicators of normal follicular
body weight extremes, liver disease, thyroid dysfunction, intrauterine contraceptive devices, stress, exercise, and 2. Non-invasive approaches which involve: Sperm counts and blood gonadotropins level.

I
function.
I

marital status. I. Flow cytometry: Flow cytometric analyses of the testes can be used to evaluate in particular the effects of toxicants • N.B: Estradiol and progesterone receptors are especially important because chemicals (e.g., DDT and
on cell size, cell shape, cytoplasmic granularity and pigmentation, measurements of surface antigens, DNA/RNA, and other organochlorine pesticides) compete for these receptors and may alter their molecular
chromatin structure. conformation.
II. Sperm counts and motility: Several factors affect the number of sperm in an ejaculate, including age, testicular size, 3. Ovulation/Fertilization/Implantation: Reproductive performance is best assessed by pregnancy, and this
frequency of ejaculation, degree of sexual arousal, and season. represents a successful index for evaluating endocrine toxicity.
• Sperm count: the concentration of sperms in the semen.
• Semen analysis: can be used as an index of testicular and posttesticular organ function.
III. Androgens and their receptors: The androgen receptor (AR) is a member of the steroid/nuclear receptor
superfamily. The two predominant naturally occurring ligands of the AR are testosterone and dihydrotestosterone.
• Androgen receptors for TS and DHT: have been used to evaluate the effects of various gonadotoxins and a number
of divalent metal ions (Hg, Cu, Cd, etc.) which can inhibit androgen receptor binding in rodent prostate glands. Also
DDT is a potent androgen receptor antagonist which affects male reproduction.
• N.B: Leydig cells function is determined by evaluating androgen level or gonadotropins.
IV. Sertoli cells biomarkers: A number of secretory products of the Sertoli cell (e.g., transferrin, ceruloplasmin, tissue
plasminogen activator, sulfated glycoproteins) have some potential for evaluating male reproductive function. Among
the secretory products of the Sertoli cell, ABP perhaps has received the most attention as a potential indicator for
detecting gonadal injury.
Lecture 11 Developmental Definitions
Toxicology II ·
Teratology of
embryonic fetal development stages
enciple
:
* Human
*
- key points &
- - -

-
-
- -

⑤ preimplantation gastulation organogenesis letogenson

S
-

*
=

--

* Critical Periods of Susceptibility & endpoint of toxicity (Developmental stage/time of exposure) extends from approx End week to 8th week of getation humans
.
in
ghtened sweep bility formations
> within
- there periode of of peak for each
susceptibility forming structure tellect of timing of exposure teatogeneity
-
on

organogenesic
are

3
,

L
-

& -

H =

* -

# = -

A
-

-
-

=
-

o
-
-

El -
-

*
d ① S
-

0-
-
&

-
-

E &
-
- Effect of dose or exposure level on teratogencity
Thalidomide
· Mechanism & Pathogenesis of Developmental toxicities(examples
S

-
-

a ⑤ -

D S
actinomycin -
-

*
*
#
-

-
-
-

#
Chloramphenical

· mechanism oftoxicity

· To

*
- -

E A
A

& = *

-
-
-

--
==

-
· Relationship between Maternal Developmental Toxicity
Placental Toxicity
*
Summary
③

&
- - -

-
-

-
-
an -

- - -

- -

& -

·
-

* -

- - - -

-
0
-

- -

2 -

-
Regulatory Guidelines for In Vivo Testing Vive
RegulatoryProtocol Guidelines for evaluation of development toxicity

#
*
-

· Elements of Risk Assessment

*
=

6
-

& -
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