GC UNIVERSITY LAHORE

SUBMITTED BY : MUHAMMAD UMAIR

SUBMITTED TO : Dr. SARA SADIQQUE

ROLL NO : 0222-BH(E)-CHEM-19

ASSIGNMENT : CARCINOGENIC AGENT AND

CARCONOTOXICITY

COURSE CODE : CHEM-4142

SUBJECT : MOLECULAR BIOLOGY

DEPARTMENT CHEMISTRY

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Table of Contents
DEFINITIONS..................................................................................................................................................2
INTRODUCTION............................................................................................................................................2
Multistage carcinogenesis.................................................................................................................................2
Exogenous agents..........................................................................................................................................2
Morphological and genetic changes..............................................................................................................3
Molecular changes..................................................................................................................................3
Factor affecting carcinogenic agent:.................................................................................................................3
Mechanism of carcinogen.................................................................................................................................3
CONSIDERATIONS....................................................................................................................................3
CLASSIFICATION CRITERIA FOR SUBSTANCES...............................................................................4
CLASSIFICATION CRITERIA FOR MIXTURES.........................................................................................3
Classification of Mixtures When Data are Available for the Complete Mixture.........................................3
Classification of Mixtures When Data are Available for All Components or Only............................4
for Some Components of the Mixture..........................................................................................................4
HAZARD COMMUNICATION......................................................................................................................5
Allocation of Label Elements.......................................................................................................................5
DECISION LOGIC AND GUIDANCE DECISION TREE............................................................................5
FOR CLASSIFICATION AS CARCINOGENS..............................................................................................5
GUIDANCE FOR THE PREVENTION OF CARCINOGENIC AGNET:.................................................6
Evaluation of the Strength of Evidence for Carcinogenicity Arising from......................................................7
Human and Experimental Data Adopted by the International Agency for.......................................................7
Research on Cancer (IARC).............................................................................................................................7
Carcinogenicity in humans...........................................................................................................................7
Carcinogenicity in experimental animals.........................................................................................................7
Observations.................................................................................................................................................8
EXAMPLES OF CLASSIFICATION OF SUBSTANCES AS......................................................................9
CARCINOGENIC............................................................................................................................................9
STUDIES OF CANCER IN HUMANS.......................................................................................................9
STUDIES OF CANCER IN EXPERIMENTAL ANIMALS.......................................................................9
Mice..........................................................................................................................................................9
Rats...........................................................................................................................................................9
OTHER DATA RELEVANT TO ITS EVALUATION OF CARCINOGENI-........................................10
CITY AND ITS MECHANISMS...............................................................................................................10
Conclusion:.....................................................................................................................................................10

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Carcinogenic Agent and Carcinotoxicity

DEFINITIONS
The term "carcinogen" denotes a chemical substance or a mixture of chemical substances
which induce cancer or increase its incidence. Substances which have induced benign and
malignant tumours in well performed experimental studies on animals are considered also to
be presumed or suspected human carcinogens unless there is strong evidence that the
mechanism of tumour formation is not relevant for humans.

Classification of a chemical as posing a carcinogenic hazard is based on the inherent

properties of the substance and does not provide information on the level of the human
cancer risk which the use of the chemical may represent.1

INTRODUCTION
Anything that has the potential to cause cancer is a carcinogen. The ability to take precise action to avoid or
reduce our exposure to substances that may cause cancer depends on our ability to recognise them as such.
Both the International Agency for Research on Cancer of the World Health Organization and the US
Department of Health and Human Services National Toxicology Program employ evidence-based methods
to compile lists of compounds that are known or reasonably anticipated to be human carcinogenic. Both list
compounds that are known or reasonably anticipated to be human carcinogenic using evidence-based
methods. Over 500 compounds have been classified as either certain, likely, or potentially carcinogenic to
people thus far. Included in this are substances like asbestos, car exhaust, processed meat, and UV rays. I
should emphasise that being exposed to a carcinogen does not guarantee that you will develop cancer. The
quantity and duration of the exposure, exposure to other environmental factors, and the person's genetic
make-up are some of the variables that affect whether a person exposed to a carcinogen will ultimately
acquire cancer.2

In both humans and animals, cancer is a leading cause of disability and demise. Age, environment, diet, and
genetic make-up all play a role in the development of cancer, whether in humans or in animals. Humans
have a significantly higher risk of getting cancer when they enter their sixth decade. In mice exposed to a
carcinogen once or repeatedly, there is a similar window of heightened sensitivity to chemically caused
tumours (s). Toxicologic pathology has made identifying possible human carcinogens in rodent bioassays a
top priority. 90% of human malignancies are thought to be brought on by chemicals, 5% by radiation, and
90% by viruses. The use of tobacco products is thought to be the root cause of 30% of illnesses, with the
remainder being brought on by chemicals found in food, environment, and lifestyle choices. Up to 8% of all
human cancers are linked to occupational chemical exposure, which highlights the significance of chemical
compounds in the genesis of cancer. Chemical carcinogens are all extremely reactive electrophiles, or
derivatives of them, containing electron-deficient atoms that can react with nucleophilic, electron-rich sites
in the cell. These DNA-damaging chemicals can generate adducts through one or more covalent bond of the
variety of nucleophilic sites that make up deoxyribonucleic acid (DNA), in particular. 1

Multistage carcinogenesis

Exogenous agents
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It is generally acknowledged that the two-stage model of carcinogenesis in mouse skin, which
typically involves a polycyclic aromatic hydrocarbon (PAH) and a phorbol ester, was the source of
the widely accepted paradigm of carcinogenesis as involving a multistage process. Morphological
parameters can be utilised to define the process because carcinogenesis in animals is susceptible to
histological study at all stages. Two-stage or multistage carcinogenesis was easily characterised in
a variety of organ locations in animals, including the liver and the bladder, with the development
of malignant tumours being the end-point. Therefore, substances like phenobarbital,
dichlorodiphenyltrichloroethane, polychlorinated biphenyls, butylated hydroxytoluene, and
estradiol benzoate were recognised as promoters of hepatocarcinogenesis. In addition to showing
the potential harm that the pertinent substances posed to humans, the pertinent experimental
findings also contributed to our current understanding of the characteristics of malignancy. Based
on the finding of certain aberrant cell populations, including chemically produced hyperplastic
nodules in the rat liver, this understanding was developed.3

Morphological and genetic changes

The association of specific carcinogens or other external agents with multistage carcinogenesis had
ceased to be relevant to our understanding of cancer formation within 20 years of the publications
described above. During the same time period, humans replaced rodents as the context in which
carcinogenesis was most understood. The discovery of multistage carcinogenesis caused by
changes in gene structure or expression rather than the action of external agents was crucial to this
move.

A significant development was Vogelstein et al association of morphological change during the

progression of colon cancer in humans with specific genetic mutation. All forms of tumours could
be treated using the theory. Harris did not include any such information in a schematic depicting
multistage carcinogenesis with relation to human lung cancer. Alternate proliferative activity is
mediated by oncogenes and tumour suppressor genes in positive and negative ways, respectively.
Traditionally, DNA obtained from tumors rather than DNA from healthy tissue accounted for the
transformation of NIH 3T3 cells through increasing proliferative activity caused by oncogene
expression. Although the binding of several chemical carcinogens to various biological
macromolecules had been variously proven over decades, carcinogen adducts in DNA were vital,
oncogene activation has indicated.4

Molecular changes

Hanahan and Weinberg distinguished the extremely broad spectrum of studies addressing the
genetics of cancer by reference to phenotype as part of a series of articles commemorating the
publication of the 100th volume of the journal Cell. In relation to certain genes or classes of genes,
six features of how cancer cells act might be found. The phenotypic traits included uncontrolled
proliferative activity, tumour growth attributable to familial risk, cancer cell survival, cancer cell
immortalization, angiogenesis, and metastatic growth.5

Factor affecting carcinogenic agent:

Environmental toxin
 Chemical
 Physical
Dietary
 Natural product in spies
 Additives

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Lifestyle
 Hormonally mediated
 Other
Mechanism of carcinogen
 Chemical Carcinogensis
 Molecular Carcinogensis
 Hormonal Carcinogensis
 Viral physical Carcinogensis
 Spontaneous Carcinogensis
These are of the following explain with the help of example and the background knowledge. The
most of these above mechanism the chemical carcinogenic agent is most worst and the highly risky
for the human and animal to cause them a cancer.

CONSIDERATIONS

The purpose of the harmonised system for the classification of chemicals which may cause
cancer is to provide common ground which could be used internationally for the
classification of carcinogenic substances.

The scheme is applicable to the classification of all chemicals.

CLASSIFICATION CRITERIA FOR SUBSTANCES

For the purpose of classification for carcinogenicity, chemical substances are allocated to
one of two classes based on strength of evidence and additional considerations (weight of
evidence). In certain instances route specific classification may be warranted.

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CATEGORY 1: KNOWN OR PRESUMED HUMAN CARCINOGENS

The placing of a chemical in Category 1 is done on the basis of epidemiological and/or

animal data. An individual chemical may be further distinguished:

CATEGORY 1A: KNOWN to have carcinogenic potential for humans; the placing of a
chemical is largely based on human evidence.

CATEGORY 1B: PRESUMED to have carcinogenic potential for humans; the placing of a
chemical is largely based on animal evidence.

Based on strength of evidence together with additional considerations, such evidence

may be derived from human studies that establish a causal relationship between human exposure
to a chemical and the development of cancer (known human carcinogen). Alternatively,
evidence may be derived from animal experiments for which there is sufficient evidence to
demonstrate animal carcinogenicity (presumed human carcinogen). In addition, on a case by
case basis, scientific judgement may warrant a decision of presumed human carcinogenicity
derived from studies showing limited evidence of carcinogenicity in humans together with
limited evidence of carcinogenicity in experimental animals.

Classification: Category 1 (A and B) Carcinogen

CATEGORY 2: SUSPECTED HUMAN CARCINOGENS

The placing of a chemical in Category 2 is done on the basis of evidence obtained from
human and/or animal studies, but which is not sufficiently convincing to place the chemical in
Category 1.

Based on strength of evidence together with additional considerations, such evidence

may be from either limited evidence of carcinogenicity in human studies or from limited
evidence of carcinogenicity in animal studies.6

Classification: Category 2 Carcinogen

Classification as Carcinogen is made on the basis of evidence from reliable and acceptable methods,
and is intended to be used for chemicals which have an intrinsic property to produce such toxic effects.
The evaluations should be based on all existing data, peer-reviewed published studies and additional
data accepted by regulatory agencies.

Carcinogen classification is a one-step, criterion-based process that involves two interrelated

determinations: evaluations of strength of evidence and consideration of all other relevant information
to place chemicals with human cancer potential into hazard classes.

Strength of evidence involves the enumeration of tumours in human and animal studies and
determination of their level of statistical significance. Sufficient human evidence demonstrates
causality between human exposure and the development of cancer, whereas sufficient evidence in
animals shows a causal relationship between the agent and an increased incidence of tumours.
Limited evidence in humans is demonstrated by a positive association between exposure and cancer,
but a causal relationship cannot be stated. Limited evidence in animals is provided when data suggest
a carcinogenic effect, but are less than sufficient. The terms "sufficient" and "limited" are used here

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as they have been defined by the International Agency for Research on Cancer (IARC) and are cited in
the Background Information for this document.7

Additional considerations (weight of evidence). Beyond the determination of the strength of

evidence for carcinogenicity, a number of other factors should be considered that influence the overall
likelihood that an agent may pose a carcinogenic hazard in humans. The full list of factors that
influence this determination is very lengthy, but some of the important ones are considered here.

 The factors can be viewed as either increasing or decreasing the level of concern for
human carcinogenicity. The relative emphasis accorded to each factor depends upon
the amount and coherence of evidence bearing on each. Generally there is a
requirement for more complete information to decrease than to increase the level of
concern. Additional considerations should be used in evaluating the tumour findings
and the other factors in a case-by-case manner.

 Some important factors which may be taken into consideration, when assessing the
overall level of concern are:
 Tumour type and background incidence.
 Multisite responses.
 Progression of lesions to malignancy.
 Reduced tumour latency.

Additional factors on which the evaluation may increase or decrease the level of concern
include:
 Whether responses are in single or both sexes.
 Whether responses are in a single species or several species.
 Structural similarity or not to a chemical(s) for which there is good evidence of
carcinogenicity.
 Routes of exposure.
 Comparison of absorption, distribution, metabolism and excretion between test
animals and humans.
 The possibility of a confounding effect of excessive toxicity at test doses.
 Mode of action and its relevance for humans, such as mutagenicity, cytotoxicity with
growth stimulation, mitogenesis, immunosuppression.8

Mutagenicity:

It is recognised that genetic events are central in the overall process of cancer development.
Therefore evidence of mutagenic activity in vivo may indicate that a chemical has a potential for
carcinogenic effects.

CLASSIFICATION CRITERIA FOR MIXTURES

Classification of Mixtures When Data are Available for the Complete Mixture.

Classification of mixtures will be based on the available test data of the individual constituents of the
mixture using cut-off values/concentration limits for the components of the mixture. The
classification may be modified on a case-by case basis based on the available test data for the mixture
as a whole. In such cases, the test results for the mixture as a whole must be shown to be conclusive
taking into account dose and other factors such as duration, observations and analysis (e.g., statistical
analysis, test sensitivity) of carcinogenicity test systems. Adequate documentation supporting the
classification should be retained and made available for review upon request.

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Classification of Mixtures When Data are not Available for the Complete Mixture.

Bridging Principles

Where the mixture itself has not been tested to determine its carcinogenic hazard, but there are
sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the
hazards of the mixture, this data will be used in accordance with the following agreed bridging rules.
This ensures that the classification process uses the available data to the greatest extent possible in
characterising the hazards of the mixture without the necessity for additional testing in animals.

Dilution

If a mixture is diluted with a diluent which is not expected to affect the carcinogenicity of other
ingredients, then the new mixture may be classified as equivalent to the original mixture.

Batching

The carcinogenic potential of one production batch of a complex mixture can be assumed to be
substantially equivalent to that of another production batch of the same commercial product produced
by and under the control of the same manufacture unless there is reason to believe there is significant
variation in composition such that the carcinogenic potential of the batch has changed. If the latter
occurs, a new classification is necessary.9

Classification of Mixtures When Data are Available for All Components or Only
for Some Components of the Mixture.

The mixture will be classified as a carcinogen when at least one ingredient has been classified as a
Category 1 or Category 2 carcinogen and is present at or above the appropriate cut-off
value/concentration limit as mentioned in Table 1 below for Category 1 and 2 respectively.

Table 1: Cut-off values/concentration limits of ingredients of a mixture classified as carcinogen

that would trigger classification of the mixture1.

Ingredient Cut-off/concentration limits triggering classification of a mixture

classified as: as:
Category 1 carcinogen Category 2 carcinogen
Category 1 0.1 %
carcinogen
0.1% (note1)
Category 2 -
carcinogen 1.0% (note 2)

Note 1: If a Category 2 carcinogen ingredient is present in the mixture at a concentration between

0.1% and 1%, every regulatory authority would require information on the MSDS for a
product. However, a label warning would be optional. Some authorities will choose to label
when the ingredient is present in the mixture between 0.1% and 1%, whereas others would
normally not require a label in this case.
Note 2: If a Category 2 carcinogen ingredient is present in the mixture at a concentration of > 1%,
both an MSDS and a label would generally be expected.10

HAZARD COMMUNICATION
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Allocation of Label Elements

Table 2: Label Elements of Carcinogenicity

Category 1A Category 1B Category 2

Symbol New health hazard New health hazard New health hazard
symbol symbol symbol

Signal Word Danger Danger Warning

Hazard Statement May cause cancer May cause cancer Suspected of causing
(state route of exposure (state route of exposure cancer (state route of
if it is conclusively if it is conclusively exposure if it is
proven that no other proven that no other conclusively proven
routes of exposure routes of exposure that no other routes of
cause the hazard) cause the hazard) exposure cause the
hazard)11

DECISION LOGIC AND GUIDANCE DECISION TREE

FOR CLASSIFICATION AS CARCINOGENS
1. SUBSTANCES

Is there documentation
showing that the substance is YES Classify
a: and label
- known or presumed human in
carcinogen? I.e. fulfil the accordanc

NO

IsThe
theresubstance
documentation showing
is not to be classified YES
Classify
that
andthe substance
labelled as aiscarcinogen
a:
and label
- suspected human carcinogen?
in
I.e. fulfil the criteria for
accordanc
category 2 see box x

2. MIXTURES
NO

Does the mixture contain one or more substance which fulfil the criteria as carcinogen in category 1 or 2 (see ab
YES More than 0,1 % of
YES Label in
category 1 or category 2
accordanc
(note1) ?
e with
Or more than 1 % of
table 1
category 2 (note 2)?
GUIDANCE FOR THE PREVENTION OF CARCINOGENIC AGNET:
NO
NO
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The mixture is not to be classified and labelled as a carcinogen
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The following additional considerations apply to classification of chemicals into either Category 1 or
Category 2. A chemical that has not been tested for carcinogenicity may in certain instances be
classified in Category 1 or Category 2 based on tumour data from a structural analogue together with
substantial support from consideration of other important factors such as formation of common
significant metabolites, e.g. for benzidine congener dyes.

The classification should take into consideration whether or not the chemical is absorbed by a given
route(s); or whether there are only local tumours at the site of administration for the tested route(s),
and adequate testing by other major route(s) show lack of carcinogenicity.

It is important that whatever is known of the physico-chemical, toxicokinetic and toxicodynamic

properties of the substances, as well as any available relevant information on chemical analogues, i.e.
structure activity relationship, is taken into consideration when undertaking classification.

It is realised that some regulatory authorities may need flexibility beyond that developed in the hazard
classification scheme. For inclusion into Safety Data Sheets positive results in any carcinogenicity
study performed according to good scientific principles with statistically significant results may be
considered.

Guidance on the importance of the different factors mentioned in paragraph 145 has to be elaborated in
order to indicate their effects or level of concern.

The relative hazard potential of a chemical is a function of its intrinsic potency. There is great
variability in potency among chemicals, and it may be important to account for these potency
differences. The work that remains to be done is to examine methods for potency estimation.
Carcinogenic potency as used here does not preclude risk assessment.

The proceedings of the recent WHO/IPCS working group to harmonised risk assessment for
carcinogenicity points to a number of scientific questions arising for classification of chemicals e.g.
mouse liver tumours, peroxisome proliferation, receptor-mediated reactions, chemicals which are
carcinogenic only at toxic doses and which do not demonstrate mutagenicity. Accordingly, there is a
need to articulate the principles necessary to resolve these scientific issues which have led to diverging
classifications in the past. Once these issues are resolved, there would be a firm foundation for
classification of a number of chemical carcinogens.

Data already generated for classifying chemicals under existing systems should be acceptable when
reviewing these chemicals with regard to classification under the harmonised system. Further testing
should not (normally) be necessary.12

Evaluation of the Strength of Evidence for Carcinogenicity Arising from

Human and Experimental Data Adopted by the International Agency for
Research on Cancer (IARC).
Carcinogenicity in humans
The evidence relevant to carcinogenicity from studies in humans is classified into one of the following
categories:
 Sufficient evidence of carcinogenicity: The Working Group considers that a causal
relationship has been established between exposure to the agent, mixture or exposure
circumstance and human cancer. That is, a positive relationship has been observed

Between exposure and cancer in studies in which chance, bias and confounding could be ruled out with
reasonable confidence.
 Limited evidence of carcinogenicity: A positive association has been observed
between exposure to the agent, mixture or exposure circumstance and cancer for

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which a causal interpretation is considered by the Working Group to be credible, but

chance, bias or confounding could not be ruled out with reasonable confidence.
In some instances the above categories may be used to classify the degree of evidence related to
carcinogenicity in specific organs or tissues.13

Carcinogenicity in experimental animals

The evidence relevant to carcinogenicity in experimental animals is classified into one of the following
categories:
 Sufficient evidence of carcinogenicity: The Working Group considers that a causal
relationship has been established between the agent and an increased incidence of
malignant neoplasms or of an appropriate combination of benign and malignant
neoplasms in (a) two or more species of animals or (b) in two or more independent
studies in one species carried out at different times or in different laboratories or
under different protocols.
 Exceptionally, a single study in one species might be considered to provide sufficient
evidence of carcinogenicity when malignant neoplasms occur to an unusual degree
with regard to incidence, site, type of tumour or age at onset.
 Limited evidence of carcinogenicity: The data suggest a carcinogenic effect but are
limited for making a definitive evaluation because, e.g., (a) the evidence of
carcinogenicity is restricted to a single experiment; or (b) there are unresolved
questions regarding the adequacy of the design, conduct or interpretation of the
study; or (c) the agent or mixture increases the incidence only of benign neoplasms
or lesions of uncertain neoplastic potential, or of certain neoplasms which may occur
spontaneously in high incidences in certain strains.14

1. A large number of chemicals have been classified as carcinogenic and placed into various
categories for labelling or other regulatory purpose. Chemicals that have been identified as
carcinogenic may also occur as components of preparations (mixtures), impurities or additives.
Gold and co-authors calculated doses from animal testing which result in tumours in half the
dosed animals (TD50 values span a range of more than eight orders of

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magnitude). Most classification systems do not take into account the wide range of potencies of these
chemicals.

2. Carcinogens are in some countries divided into three potency groups: high, medium and low.
Potency is in these instances determined using dose-response data in the observed dosing range for
laboratory animals. Additional indicators of potency such as tumour site and species specificity, or
species differences in toxicokinetics may also be used. Such potency groups are used to set upper
limits for the classification of substances as carcinogens and for the purpose of initiating labelling.
They have also been used for the classification and determination of labelling provisions for
preparations (mixtures) of carcinogenic chemicals.

3. Some countries have implemented a scheme where 0.1% is used as a default limit value for
labelling of substances and preparations (mixtures) as carcinogens with sufficient data for
carcinogenicity. In these countries chemicals with medium carcinogenic potency are labelled if
they occur in chemical substances at or above this level. Many carcinogenic compounds fall into
the medium range. Carcinogens with high potency might be classified and labelled at lower levels
and carcinogens with low potency could be classified and labelled only when they occur at higher
levels. Some countries use 1% as a default limit value for low potency carcinogens and for
carcinogens with more limited data.

4. Some regulatory authorities do not have the obligation to perform potency determinations. If
a chemical carcinogen is a candidate for a potency rating outside of the default range, such
chemicals should be referred to an international group for its determination.

Observations
5. The Working Group agreed that it would be useful to explore further the concept of using
potency to make labelling decisions. Initial thoughts of the Working Group are presented here.

6. Potency ranking of carcinogens should not be determined or refined more precisely than by
ten-fold factors in light of differences in species response, tumour types and the limits of
standardisation of test protocols. In light of these points, a scheme for classification and labelling
purposes which separates carcinogens into potency groupings serves the practical purposes listed
above.

7. The use of potency for establishing limits does not preclude the ability of authorities to
perform quantitative risk assessments of exposures to carcinogenic substances for regulatory
purposes.

8. Potency determinations should be based on well performed studies which are peer reviewed,
performed according to good laboratory practices, or are deemed acceptable by regulatory
authorities.

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EXAMPLES OF CLASSIFICATION OF SUBSTANCES AS

CARCINOGENIC

STUDIES OF CANCER IN HUMANS

Cohort study

A cohort of 587 male workers was set up at a plant manufacturing ARA including all employees
working in 1980 at the time when the cohort was established and all past employees in the
manufacturing process since 1965. The mortality was assessed up to the end of 1990. 2.5% of the
cohort could not be traced. Reference rates from the countries were obtained. Overall, 63 deaths
occurred versus 69.5 expected (standard mortality ratio [SMR], 0.9 [95% confidence interval (CI),
0.8-1.0]) including 25 cancer deaths versus 22.2 expected (SMR, 1.1 [95% CI, 0.7-1.5]). When a
10-year latency was imposed between the start of exposure and start of follow up, an excess of
mortality from bladder cancer was observed (SMR, 2.3 [95% CI, 0.8-4.2]), increasing to 3.3 after
15 years. Additional analysis by job and categories of exposure to chemicals did not identify any
risk factor for bladder cancer. An examination of the exposure level and time since exposure of the
bladder cancer did not support a causal interpretation.

STUDIES OF CANCER IN EXPERIMENTAL ANIMALS

Mice

Groups of 50 male and 50 female B6C3F1 mice, six weeks of age, were administered ARA
(purity, >99%) in the diet at 0, 1500 or 3000 ppm for 102-103 weeks. Mean body weights of both
treated males and females were lower than those of the corresponding controls. Mortality was not
significantly related to treatment in either sex. In male mice, the incidence of haemangiomas or
haemangiosarcomas (combined, all sites, mainly observed in the abdominal viscera) was
increased: 2/49 (4%), 4/50 (8%) and 12/50 (24%) (p<0.002, Cochran-Armitage trend test) in
control, low-dose and high-dose groups, respectively. In female mice, the incidence of
hepatocellular adenomas or carcinomas (combined) was increased: 0/50 (0%), 4/49 (8%) and
13/50 (26%; p<0.007, Fisher’s exact test; p = 0.001 trend test) in control, low-dose and high-dose
groups, respectively (1).

Rats

Groups of 50 male and 50 female Fischer 344 rats, six weeks of age, were administered ARA
(purity, >99%) in the diet at concentrations of 0, 2000 or 4000 ppm for 102-103 weeks. Mean
body weights of treated male and female rats were lower than those of the corresponding controls.
Mortality was not significantly affected by the treatment. In male, the incidence of sarcomas,
fibrosarcomas, angiosarcomas or osteosarcomas (combined) of multiple organs was 0/50 (0%),
15/50 (30%; p = 0.003, Fisher’s exact test) and 40/50 (80%; p>0.001); and that of mesotheliomas
of multiple organs or tunica vaginalis was 0/50 (0%), 18/50 (p<0.001, Fisher’s exact test) and
22/50 (44%; p<0.001) in control, low- and high-dose groups, respectively. In females, the
incidence of transitional cell carcinomas of the urinary bladder was 0/50 (0%), 9/45 (20%; p =
0.03) and 25/50 (50%; p<0.001); that of sarcomas, fibrosarcomas, osteosarcomas or
angiosarcomas (combined) of multiple organs was 0/50 (0%), 5/50 (10%) and 22/50 (44%; p =
0.001) (2).
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OTHER DATA RELEVANT TO ITS EVALUATION OF CARCINOGENI-

CITY AND ITS MECHANISMS

1.1 Genetic and related effects

See evaluation of mutagenicity. Bacterial assay system showed negative or at most

weakly positive results. In cultured mammalian cells, ARA caused sister-chromatid
exchanges and some times also increased gene mutation, chromosomal aberration and
micronuclei. The substance induced anaploidy and increased cell transformation in
mammalian cells. In rodent models in vivo, it enhanced sister-chromatid exchange and
micronuclei formation.

2. EVALUATION

 Only one epidemiological study was available for evaluation. In cohort study in a
factory producing ARA, an increase in bladder cancer was observed. However, an
examination of the exposure levels and time since exposure of the bladder cancer cases
did not support a causal interpretation. The study provides inadequate evidence in
humans for carcinogenicity.

 ARA was tested for carcinogenicity in one experiment in mice and one in rats. After oral
administration to mice, it induced haemangiomas and haemangiosarcomas and
hepatocellular carcinomas or adenomas. In rats, it increased the incidence of tumours in
multiple organs, including sarcomas, mesotheliomas and transitional-cell carcinomas of
the urinary bladder. The two studies provide sufficient evidence for carcinogenicity in
experimental animals.

 Studies on genotoxicity and mutagenicity demonstrated mutagen effects in mammalian

cells in vitro as well as formation of sister chromatid exchanges and micronuclei in vivo
in rodents. The studies provide evidence that genotoxic mechanisms may be involved in
the induction of tumours.16
Conclusion:
Carcinogenic agent are the main source of cancer causing and the effect of these agent cause serious
effect. The chemical, molecular, hormonal, and other is the main mechanism for the cancer causing
which may be benign and malignant cancer and that all is describe with the help of example and the
background and latest knowledge briefly.
1. REFERENCES
1. Pott, F. Fiber as a carcinogenic agent. Zentralblatt fur Bakteriologie, Mikrobiologie und Hygiene.
Serie B, Umwelthygiene, Krankenhaushygiene, Arbeitshygiene, Praventive Medizin 184, 1–23 (1987).
2. Smith, M. T. Quinones as mutagens, carcinogens, and anticancer agents: introduction and overview.
(1985).
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