Carcinogenicity
Carcinogenic substances are substance which induce
(malignant) tumours, increase their incidence or malignancy, or shorten the
time of tumour occurrence after inhalation, ingestion, dermal application or
injection. It is generally accepted that carcinogenesis is a multihit/
multi-step process from the transition of normal cells into cancer cells via a
sequence of stages and complex biological interactions, strongly influenced by
factors such as genetics, age, diet, environment, hormonal balance, etc.
(malignant) tumours, increase their incidence or malignancy, or shorten the
time of tumour occurrence after inhalation, ingestion, dermal application or
injection. It is generally accepted that carcinogenesis is a multihit/
multi-step process from the transition of normal cells into cancer cells via a
sequence of stages and complex biological interactions, strongly influenced by
factors such as genetics, age, diet, environment, hormonal balance, etc.
Since the induction of cancer involves genetic alterations which can be induced
directly or indirectly, carcinogens have conventionally been divided into two
categories according to their presumed mode of action: genotoxic carcinogens
and non-genotoxic carcinogens.
Genotoxic
Carcinogens
Carcinogens
They have the ability to interact with DNA and/or
the cellular apparatus (such as e.g.
the spindle apparatus and topoisomerase enzymes) and thereby affect
the integrity of the genome.
the cellular apparatus (such as e.g.
the spindle apparatus and topoisomerase enzymes) and thereby affect
the integrity of the genome.
Non-genotoxic
Carcinogens
Carcinogens
They exert their carcinogenic effects through other
mechanisms that do not involve direct alterations in DNA.
mechanisms that do not involve direct alterations in DNA.
The complexity of the carcinogenicity process makes
it difficult to develop in vitro
alternative test models that mimic the full process, especially for
non-genotoxic chemicals. The challenge in developing in vitro
alternatives is also heightened because of the complexity of the number of
target organs. It is expected that an integrated approach involving multiple in vitro models will be needed, but a
better understanding of the entire process is needed before this will be
possible . While in vitro and in vivo genotoxicity tests contribute to the
assessment of genotoxic carcinogens, there is a lack of tests available for the
assessment of non-genotoxic carcinogens.
it difficult to develop in vitro
alternative test models that mimic the full process, especially for
non-genotoxic chemicals. The challenge in developing in vitro
alternatives is also heightened because of the complexity of the number of
target organs. It is expected that an integrated approach involving multiple in vitro models will be needed, but a
better understanding of the entire process is needed before this will be
possible . While in vitro and in vivo genotoxicity tests contribute to the
assessment of genotoxic carcinogens, there is a lack of tests available for the
assessment of non-genotoxic carcinogens.
Mutagenesis
The induction of genetic change in a cell
by the alterations in the cell’s genetic material (usually deoxyribonucleic acid [DNA]) is referred to
as mutagenesis. This change or alteration can subsequently be inherited
from one cell to the next. While many mutations are benign, some can be
detrimental and cause human genetic disease.
If the mutation occurs in a gamete
(sex cell), the genetic alteration may be passed to subsequent generations.
Mutations provide a mechanism for evolution if the mutations in the DNA produce a new or
modified protein that has enhanced or new beneficial functions such that this
newly acquired characteristic has a selective survival advantage and thus will
be more likely to be passed down from one generation to the next. However,
there are cells which will not have the potential to develop into any other
cell types because they are usually spontaneous and not inherited. This is as a
result of mutations in somatic cells, or cells that have undergone
differentiation
by the alterations in the cell’s genetic material (usually deoxyribonucleic acid [DNA]) is referred to
as mutagenesis. This change or alteration can subsequently be inherited
from one cell to the next. While many mutations are benign, some can be
detrimental and cause human genetic disease.
If the mutation occurs in a gamete
(sex cell), the genetic alteration may be passed to subsequent generations.
Mutations provide a mechanism for evolution if the mutations in the DNA produce a new or
modified protein that has enhanced or new beneficial functions such that this
newly acquired characteristic has a selective survival advantage and thus will
be more likely to be passed down from one generation to the next. However,
there are cells which will not have the potential to develop into any other
cell types because they are usually spontaneous and not inherited. This is as a
result of mutations in somatic cells, or cells that have undergone
differentiation
Alteration of an individual gene,
or a specific letter in the DNA alphabet called a nucleotide can result from
mutagenesis. There are four nucleotides, adenine, guanine, cytosine, and
thymine. Mutagenesis—or the process acquiring mutations—can be in the form of a
point mutation, a deletion, or a duplication in the DNA sequence. A single
nucleotide change, called a point mutation, can cause a genetic disease if it
occurs in a gene important for normal cellular function. Deletions involve
deleted sequence of DNA that can be in a coding gene sequence (called an exon)
or a noncoding sequence of the gene (called an intron) or the noncoding
sequence that separates genes. Deletions can be in a single nucleotide or span
several genes. There is a repeat sequence of DNA referred to as DNA
duplications.
or a specific letter in the DNA alphabet called a nucleotide can result from
mutagenesis. There are four nucleotides, adenine, guanine, cytosine, and
thymine. Mutagenesis—or the process acquiring mutations—can be in the form of a
point mutation, a deletion, or a duplication in the DNA sequence. A single
nucleotide change, called a point mutation, can cause a genetic disease if it
occurs in a gene important for normal cellular function. Deletions involve
deleted sequence of DNA that can be in a coding gene sequence (called an exon)
or a noncoding sequence of the gene (called an intron) or the noncoding
sequence that separates genes. Deletions can be in a single nucleotide or span
several genes. There is a repeat sequence of DNA referred to as DNA
duplications.
The major cause of mutagenesis is due to exposure
to ionizing radiation
and certain chemicals. Ionizing radiations include cosmic rays, x rays,
and ultraviolet light.
It is of interest to note that melanoma, caused almost exclusively by exposure
to the ultraviolet radiation from the sun,
is the most rapidly increasing lethal cancer
in the world. In melanoma, ultra violet radiation induces what is called
thymine dimers. This means that two thymine nucleotides next to each other in a
DNA sequence form an abnormal bond. Thymine dimers in a skin cell can lead to
skin cancer. The depletion of ozone layer and consequent increased exposure of
ultraviolet radiation of the skin heightened prevalence of melanoma
to ionizing radiation
and certain chemicals. Ionizing radiations include cosmic rays, x rays,
and ultraviolet light.
It is of interest to note that melanoma, caused almost exclusively by exposure
to the ultraviolet radiation from the sun,
is the most rapidly increasing lethal cancer
in the world. In melanoma, ultra violet radiation induces what is called
thymine dimers. This means that two thymine nucleotides next to each other in a
DNA sequence form an abnormal bond. Thymine dimers in a skin cell can lead to
skin cancer. The depletion of ozone layer and consequent increased exposure of
ultraviolet radiation of the skin heightened prevalence of melanoma
Tumour suppressor genes can be affected by mutation
resulting in uncontrollable cellular growth, also called cancer. If this cancer
is not detected early and removed, it can become vascularized and leak into the
bloodstream. If it metastizes in this way, the cancer can quickly spread to
other organs. Additionally, a number of chemicals have been identified as
mutagenic such as the common household cleaner bleach.
Many chemicals intercalate into the DNA double helix and cause errors
during DNA replication. Chemicals that bind
to DNA are called DNA adducts. Mutagenesis is induced by many environmental
carcinogens or cancer-causing chemicals
resulting in uncontrollable cellular growth, also called cancer. If this cancer
is not detected early and removed, it can become vascularized and leak into the
bloodstream. If it metastizes in this way, the cancer can quickly spread to
other organs. Additionally, a number of chemicals have been identified as
mutagenic such as the common household cleaner bleach.
Many chemicals intercalate into the DNA double helix and cause errors
during DNA replication. Chemicals that bind
to DNA are called DNA adducts. Mutagenesis is induced by many environmental
carcinogens or cancer-causing chemicals
One mechanism, called nucleotide excision repair,
involves recognition and removal of damaged DNA by nicking it where there is a
point mutation, removing the damaged nucleotide sequence, re-synthesis to add
the correct nucleotide, and DNA ligation of the nicked DNA to seal the DNA
where it is being repaired. Despite the many different ways that mutagenesis
can occur, mechanisms for DNA repair exist that help maintain the integrity of
the genome.
involves recognition and removal of damaged DNA by nicking it where there is a
point mutation, removing the damaged nucleotide sequence, re-synthesis to add
the correct nucleotide, and DNA ligation of the nicked DNA to seal the DNA
where it is being repaired. Despite the many different ways that mutagenesis
can occur, mechanisms for DNA repair exist that help maintain the integrity of
the genome.
Reproductive
Toxicity
Toxicity
Reproductive toxicology is the toxicity of
chemicals on fertility and sexual function of organism. This can be due to
exposure of hazardous substances during prenatal period. It is a special part
of toxicology which comprises any effect of chemicals and active substances on
mammalian reproduction (fertility, weaning) and development (embryonal and
fetal development). Reproductive it can also be referred to as the toxic
effects of various substances on reproductive ability of an organism. In other
words it can also be called as developmental toxicology.
chemicals on fertility and sexual function of organism. This can be due to
exposure of hazardous substances during prenatal period. It is a special part
of toxicology which comprises any effect of chemicals and active substances on
mammalian reproduction (fertility, weaning) and development (embryonal and
fetal development). Reproductive it can also be referred to as the toxic
effects of various substances on reproductive ability of an organism. In other
words it can also be called as developmental toxicology.
Several methods are used to determine the
reproductive toxicity of various substances. The major test is developmental
toxicity screening assay. The investigations and the interpretation of the
results should be related to all other pharmacological and toxicological data
available to determine the risk of the test compound to humans. Observations of
this are best measured in a close study of all stages of development from
conception of one generation to conception of the following generation(s) to
allow detection of immediate and latent effects of exposure which covers one
complete life cycle from the mature adult.
reproductive toxicity of various substances. The major test is developmental
toxicity screening assay. The investigations and the interpretation of the
results should be related to all other pharmacological and toxicological data
available to determine the risk of the test compound to humans. Observations of
this are best measured in a close study of all stages of development from
conception of one generation to conception of the following generation(s) to
allow detection of immediate and latent effects of exposure which covers one
complete life cycle from the mature adult.
