19 Types of Exposure and toxic response

Question 1

4 types

Different types of toxicities could be…

Answer 1

• Carcinogenicity
• Teratogenicity
• Mutagenicity
• Genotoxicity

Question 2

define, classification of a chem is based on, repeated or long exposure

Carcinogenicity

Answer 2

• Carcinogen is a chemical substance or a mixture of chemical substances which induce cancer or increase its incidence
• Classification of a chemical as a carcinogen is based on the inherent properties of the substance and does not provide information on the level of human cancer risk its use may represent
• Carcinogens are chronic toxins causing damage after repeated or long-duration exposure
  -May not have immediate apparent harmful effects, with cancer developing only after a long latency period

Question 3

Carcinogenic agent

Answer 3

Chemical – Most mutagenic agents
Physical – Ionizing radiation, UV radiation, asbestos
Biological – Oncogenic viruses, e.g. human T-leukemia virus

Question 4

Classes of chemicals as carcinogens

Answer 4

• Epoxides: Ethylene oxide
• Organohalogen compounds: Chloroform
• Hydrazines: Hydrazine
• N-Nitroso compounds: N-Nitrosodimethylamine
• Aromatic Amines: Benzidine
• Aromatic hydrocarbons: Benzene
• Miscellaneous organic compounds: Formaldehyde
• Miscellaneous inorganic compounds: Chromium and compounds

Question 5

How do carcinogens enter the body?

Answer 5

• Skin absorption: Many solvents and other chemicals go directly through the skin
• Ingestion: Swallowing of a carcinogen
• Inhalation: Breathing gases, fumes and vapors is the most common form of exposure

Question 5

What organs are prone to carcinogens attack?

Answer 5

Lungs
Liver
Kidney
Reproductive system
Skin
Many other organs and tissues

Question 5

Epidemiological studies, animal studies, Direct evaluation of carcinogen

How is carcinogenicity determined?

Answer 5

1. Epidemiological studies
   Determine relationship between a suspect chemical and human population over a long period of time
2. Animal studies
   -Directly induce cancer in test animals using large sample of animals
   -Usually of two or more species with varying dose and time
   -Based on the premise that chemicals that produce cancer in animals will have similar effects on human cells
   -Most known human carcinogens produce cancer in experimental animals
3. Direct evaluation of carcinogenicity
   * Laboratory tests
   -In animals
   -In vitro transformation of cultivated cells
   * Epidemiologic studies of exposed human population

Question 6

dose and environmental

Factors influencing the development of cancer

Answer 6

• Dose: Amount and length of exposure
• Environmental or “lifestyle” factors
  -Cigarette smoking (co-carcinogen),
  -Alcohol consumption (co-carcinogen),
  -Diet: High fat consumption, natural antioxidants,
  -Geographic location: Industrial areas, UV light,
  -Therapeutic drugs: Some are known carcinogens,
  -Inherited conditions.

Question 7

definition, non rev, agents, major malformations

Teratogenicity

Answer 7

• It is the ability to cause developmental anomalies in afoetus
• Non reversible functional or morphological defects present at birth which…
  -May be visible at birth
  -May only become evident later in life
• Agents that cause developmental abnormalities are known as teratogens
  -Include viruses, chemicals, and radiation
• Their study is known asteratology
• Teratogenicity is the presence of major congenital malformations
• Major malformations are those that are either life-threatening, require major surgery, or have serious cosmetic effects
• The more inclusive term of all these major defects is “congenital anomalies” or “birth defects”

Question 8

Causes of malformations

Answer 8

• 40% - Unknown
• 12–25% - Genetic defects (Down’s syndrome is the most common of this group)
• 20% - Interactions between hereditary factors and environmental factors
• 5–9% - Environmental factors such as maternal disease or infection, chemicals, X-ray and drugs

Question 9

Environmental factors causing teratogenecity

Answer 9

• Maternal disease such as diabetes and seizure disorders
• Infections such as rubella (German measles)
  -Maternal rubella can result in a group of defects, including heart disease, cataracts and deafness, known as foetal rubella syndrome
• Chemicals and drugs: Only a small portion are due to drugs acting as teratogens

Question 10

The risk of teratogenicity

Answer 10

-There is no way to predict drug exposures that result in teratogenesis
-Several factors determine the teratogenic effects of drugs on the foetus during pregnancy
-The effects of many drugs on animal development are not applicable to human pregnancies

Question 11

Factors that determine the effects of teratogens

Answer 11

1. Dose reaching foetus
2. Point in development when drug exposure occurs
3. Duration of exposure
4. Environmental factors e.g. age or disease of the mother
5. Susceptibility of the foetus

Question 12

The duration of exposure and gestational age at exposure
- teratogenecity

Answer 12

• These are very critical in the determination of teratogenic potential
• During the period from conception to implantation (2–3 weeks), there is a relative resistance to drug effects
• Exposure during this time produces an “all or none” effect (zygote dies or it is unaffected)

Question 13

week, drugs that reach embryo

Organogenesis
- teratogenecity

Answer 13

Weeks 4 through 10 (remainder of first trimester): the period referred to as organogenesis
-The most critical time for organ malformation
-Unfortunately, this is also a time when many women are unaware of their pregnancy

Drugs that reach the embryo at this point may produce
-Abortion
-No effect at all
-An anatomic defect (teratogenesis), or
-A metabolic or functional defect that may not be detected until later in life

Question 14

Foetal stage (Foetogenesis)
- teratogenecity

Answer 14

During the second and third trimester
-Drugs are not associated with major malformations
-But may influence neurologic development, growth, physiologic and biochemical functioning, mental development, and reproduction
Little is known about the exact time of the greatest risk for teratogenesis

An exception is thalidomide, which has been shown most harmful during days 34-56 of gestation
i.e., weeks 5–8

Question 15

what was the most common birth defect

Answer 15

Phocomelia was the most visible of the birth defects that occurred in many children whose mothers took the drug thalidomide during pregnancy
-Phocomelia is a condition in which the long bones of the limbs are deficient or absent

Question 16

3 syndromes

Teratogenic effects

Answer 16

Some drugs cause a group of effects specific for exposure to that agent

These congenital anomalies are named after the drug known to cause them:
“Foetal alcohol syndrome”
“Foetal warfarin syndrome” or
“Foetal hydantoin syndrome”

Question 17

Foetal alcohol syndrome

Answer 17

This group of defects is seen in mothers with high-dose alcohol intake during their pregnancies

May result in several of the following:
Prenatal and postnatal growth retardation, mental retardation, poor coordination, hypotonia, hyperactivity, microcephaly, short upturned nose, micrognathia or retrognathia in infancy, short palpebral fissures, hypoplastic philtrum, thinned upper lips, and, less frequently, anomalies of the eyes, mouth, heart, kidneys, gonads, skin, muscle, and joints

Question 18

Foetal warfarin syndrome

Answer 18

The anomalies include nasal hypoplasia, depressed bridge of nose, and bone stippling on x-ray (seen with first trimester exposure)

A distinctly different pattern is seen with second- and third-trimester exposure to coumarins, featuring optic atrophy, cataracts, mental retardation, microcephaly, microphthalmia, deafness, growth retardation, scoliosis (curvature of the spine), seizures and haemorrhage

Question 19

Known teratogens and their effects

Answer 19

• Aminoglycosides (high dose): VIII cranial nerve damage
• Androgens: Masculinization of female foetus
• ACE inhibitors: Renal tubular dysplasia, skull hypoplasia oligohydramnios, pulmonary hypoplasia
• Antineoplastics
  -Alkylating agents: Growth retardation, cleft palate, microphthalmia, cloudy cornea, agenesis of kidney, cardiac defects
  -Antimetabolite agents: Growth retardation, malformation of ear, eye, nose, cleft palate, malformation of extremities, fingers, brain, skull
• Carbamazepine: Craniofacial abnormalities, growth retardation, neural tube defects, fingernail hypoplasia
• Cocaine: Premature birth, abruptio placentae, perinatal morbidity, growth retardation, in utero stroke, bowel atresias, defects of genitourinary system, heart, limb, face
• Tetracyclines: Weakend foetal bone and tooth enamel dysplasia, permanent tooth discoloration
• Thalidomide: Phocomelia and amelia, deafness anomalies of teeth, eyes, intestines, heart, kidney

Question 20

Teratogenicity studies

Answer 20

-Animal studies cannot be true predictors of teratogenicity due to wide inter- and intraspecies variations in the pharmacokinetic properties of drugs, including placental transfer
-Only controlled epidemiological studies can detect a relationship between environmental factors such as drug exposure and pregnancy outcomes

Question 21

Drug Risk Category
- teratogenecity

Answer 21

A. No foetal risk shown in controlled human studies in all trimesters. Possibility of harm to foetus is remote
B.Animal studies show a risk that is not confirmed in human studies during all trimesters
C. Foetal risk shown in controlled animal studies but no controlled human studies are available OR
Studies in humans and animals are not available
Drugs only given if the potential benefit outweighs the potential risk to the foetus
D. Studies show foetal risk in humans (Use of drug may be acceptable even with risks, such as in life-threatening illness or where safer drugs cannot be used or are ineffective)
E. Risk to foetus outweighs any benefits from these drugs
The drug is contraindicated in women who are or may become pregnant

Question 22

Mutagenicity

Answer 22

• Mutagenicity refers to the induction of permanent transmissible changes in the structure of the genetic material
• Mutation is replacement of nitrogen base with another in one or both the strands or addition or deletion of a base pair in a DNA molecule
• Substance (chemicals) which can induce mutations are collectively known as mutagens

Question 23

mutagenecity - 2 classes

Classes of mutations

Answer 23

1. Spontaneous mutation: They are mainly caused during DNA replication or by incorporation of incorrect nucleotide in the growing DNA chain. They occur by changes in DNA sequence.
2. Induced mutation: They are caused by the changes in DNA brought by some environmental factors called mutagens.
   E.g. UV Light

Question 24

2 types

Types of mutations

Answer 24

1. Point mutation
   -Change/substitution in a single nucleotide
   E.g. sickle cell disease
2. Frame shift
   -Insertion or deletion of one/more nucleotides
   -Changes the reading frame

Question 24

Genotoxicity

Answer 24

It is a broader term that refers to ability of an agent to interact with DNA and/or the cellular apparatus that regulates the genome, such as the spindle apparatus and topoisomerase enzymes
It is similar to mutagenicity except that genotoxic effects are not necessarily always associated with mutations. All mutagens are genotoxic, however, not all genotoxic substances are mutagenic.

Question 25

* Mutagenicity testing with prokaryotic cell system:

-Ames test
-Host m

Mutagenicity testing

Answer 25

Ames test
Developed by Bruce Ames
Test system – Auxotrophic strains of Salmonella tyhpimurium – survives only in a medium with histidine (dies in normal medium without histidine)
After treatment with mutagen some auxotrophic cells revert back to normal wild phenotype which can synthesize histidine and survive in a medium lacking histidine
These cells are called revertants (due to reverse mutation)

Host mediated assay
Salmonella injected intra-peritoneally into rat or a hamster
The animal is treated with the test substance orally
Afterwards sample is withdrawn from peritoneal cavity and mutation in Salmonella is measured

Saccharomyces forward-mutation assay
A variety of haploid and diploid strains of the yeast Saccharomyces cerevisiae can be used to measure the production of gene mutations
Forward mutation systems in haploid strains such as measurement of mutation from red pigment producing, adenine requiring mutants (ade-1 , ade-2) to double adenine-requiring white mutants
Colonies that grow on a low adenine medium are white following mutation