19 Types of Exposure and toxic response Flashcards
(30 cards)
4 types
Different types of toxicities could be…
- Carcinogenicity
- Teratogenicity
- Mutagenicity
- Genotoxicity
define, classification of a chem is based on, repeated or long exposure
Carcinogenicity
- 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
Carcinogenic agent
Chemical – Most mutagenic agents
Physical – Ionizing radiation, UV radiation, asbestos
Biological – Oncogenic viruses, e.g. human T-leukemia virus
Classes of chemicals as carcinogens
- 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
How do carcinogens enter the body?
- 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
What organs are prone to carcinogens attack?
Lungs
Liver
Kidney
Reproductive system
Skin
Many other organs and tissues
Epidemiological studies, animal studies, Direct evaluation of carcinogen
How is carcinogenicity determined?
-
Epidemiological studies
Determine relationship between a suspect chemical and human population over a long period of time -
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 -
Direct evaluation of carcinogenicity
* Laboratory tests
-In animals
-In vitro transformation of cultivated cells
* Epidemiologic studies of exposed human population
dose and environmental
Factors influencing the development of cancer
- 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.
definition, non rev, agents, major malformations
Teratogenicity
- 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”
Causes of malformations
- 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
Environmental factors causing teratogenecity
- 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
The risk of teratogenicity
-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
Factors that determine the effects of teratogens
- Dose reaching foetus
- Point in development when drug exposure occurs
- Duration of exposure
- Environmental factors e.g. age or disease of the mother
- Susceptibility of the foetus
The duration of exposure and gestational age at exposure
- teratogenecity
- 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)
week, drugs that reach embryo
Organogenesis
- teratogenecity
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
Foetal stage (Foetogenesis)
- teratogenecity
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
what was the most common birth defect
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
3 syndromes
Teratogenic effects
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”
Foetal alcohol syndrome
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
Foetal warfarin syndrome
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
Known teratogens and their effects
- 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
Teratogenicity studies
-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
Drug Risk Category
- teratogenecity
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
Mutagenicity
- 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
