Carcinogenic, genetic, toxic,

teratogen compounds and the

mechanisms
TIK:
to explaining carcinogenic, genetic, toxic and
teratogen compounds in depth and to known
that compounds and the mechanisms.

Toxic Effects
Carcinogenicity - Carcinogen- Any
chemical or process involving chemicals
that induces neoplasms that are not usually
observed, the earlier induction of
neoplasms
than are commonly observed, and/or the
induction of more neoplasms than are
usually found

Toxic Effects
Mutagenicity- Mutagen- Mutations are
heritable changes produced in the genetic
information stored in the DNA of living
cells. Chemicals capable of causing such
changes-Mutagens., the process is known
as
Mutagenesis.

Toxic Effects
Teratogenicity-Teratogen- Teratogenesis
The production of defects in the
reproduction process resulting in either
reduced productivity due to fetal or
embryonic mortality or the birth of
offspring with physical, mental,
behavioral, or developmental defects.
Compounds causing such defects are
known as teratogens

Thalidomide
Introduced in 1956 as
sedative (sleeping pill) and to
reduce nausea and vomiting
during pregnancy
Withdrawn in 1961
Discovered to be a human teratogen
causing absence of limbs or limb
malformations in newborns
5000 to 7000 infants effected
Resulted in new drug testing rules

Human Cancer Awareness

1700 Occupational cancer
High incidence of breast cancer
among nuns
1775 Percivall Pott
Occupational cancer of scrotum
in chimney sweeps
1895 Bladder cancer in workers
in aniline dye industry

Animal Cancer Models

1915 skin tumors in rabbits treated
with coal tar on the skin
1930s isolation of polycyclic
aromatic hydrocarbon from coal tar
1932 benzo(a)pyrene synthesized
1935 feeding azo dyes to rats can
cause liver cancer

Recent Awareness

300 million tons of organic

chemical manufactured each year
100,000+ compounds

What is Cancer?
Cancer is the uncontrolled
multiplication of cells.
Benign cancerous cells are
contained in one place
Malignant cancerous have
spread to other areas

Case Studies - Soot

1775 Percivall Pott Occupational
cancer of scrotum in chimney sweeps
1892 scrotal cancer rare on European
content but still high in England
attributed to hygiene
1915 skin tumors in rabbits treated with
coal tar on the skin
1930s isolation of polycyclic aromatic
hydrocarbon from coal tar
Now smoking and organic fuels

Case Studies - Benzene

C6H6 Clear, colorless, high flammable,
vaporizes at room temp
Known human carcinogen effect bone
marrow causing leukemia
Acute inhalation CNS effects, dizziness
In US gasoline 2% benzene but up to 5% in
other countries
Metabolized by liver to more toxic metabolites
US EPA water standard 0.005 mg/L (5 ppb)
US OSHA 1 ppm in workplace air over 8 hrs

Case Studies - Asbestos

Cause serious lung disease
Asbestosis scarring of the lung
Mesothelioma cancer of lung lining
Known since ancient times commercial use
started in early 1900s with wide spread use
during World War II
Used in 1000s of consumer and industrial
products
First heath effects seen in early 1900s
Dose response and latency effects established
in 1930s
Regulation and banning started in 1970s
Millions of people exposed

Case Studies - Radon

1400s lung disease in miners
1879 lung cancer in European Miners
Colorless, odorless radioactive gas
Decay product uranium to radium to the
gas radon to the solid polonium
Polonium sticks to lung tissue decays
releasing an alpha particle which
damages cellular DNA causing cancer
1 in 15 (6%) homes in US elevated Radon
U.S. EPA action level 4 pCi/L

Radon US Map

Environmental Factors and Cancer Deaths

Diet
Tobacco
Infection
Alcohol
Reproductive and sexual behavior
Occupation
Pollution
Geophysical factors
Medicines and medical procedures
Industrial Products

35% (10-70%)
30% (25-40%)
10% (?)
3% (2-4%)
7% (1-13%)
4% (2-8%)
2% (<1-5%)
3% (2-4%)
1% (0.5-3%)
1% (<1-2%)

Adapted from Doll and Peto, 1981; Casarett and Doulls Toxicology, 5th Ed.

Tobacco

Cancer Death Rates by Site Male

80

Rates per 100,000 and are age adjusted to the 1970 census population

60

Lung
Stomach

40

ColonandRectum
Prostate

20

Pancreas
0
1930

1940

1950

1960

1970

1980

1990

Cancer Death Rates by Site Female

Rates per 100,000 and are age adjusted to the 1970 census population

30

Lung

Breast

20

Uterine

Stomach
10

Colon&Rectum

Ovarian
Pancreas

0
1930

1940

1950

1960

1970

1980

1990

Exposure Issues

Home environment
Current events
Workplace
School
Government Decisions
Global and local environment

Time of Exposure
During Fetal Development
Rapidly dividing cells
Infancy (soy formula?)
Childhood
Puberty
Occupational exposure

What causes cancer?

Organic chemicals
Inorganic chemicals
Fiber
Radiation (EMF?)
Hormonal Carcinogenesis
Mixtures Multiple
Exposures

What causes cancer?

Internal factors
hormones
immune conditions
inherited conditions (genetics)

External factors
lifestyle habits (smoking, diet,
alcohol)
viruses, chemicals, radiation

Genetic Factors
Breast Cancer --Less 1 in 10 cases in women
with a genetic predisposition

Environmental factors?

Endocrine / Estrogenic
Pharmaceuticals
Steroidal estrogens (NTP & IRAC
lists as know human carcinogen)

Diethylstilbestrol

Chemicals
Pesticides dieldrin, atrazine
Plastic additives
bispenoal-A (BPA)
polyvinyl cloride (PVC)

Chemical Agents
Gasoline additives benzene
Solvents & degreasing agents
Polycyclic aromatic hydrocarbons
(PAHs)
Cigarettes / tobacco products
Phthalates
PBDEs?
PCBs, DDT, DDE

Rates of Death Due to Cancer,* United States, 1999

154.7-193.7

194.5-206.5

207.8-214.0

214.8-236.9

*Deaths per 100,000 people, age adjusted to 2000 total U.S. population.
Data are grouped in quartiles and ranked from lowest to highest.
Source: National Center for Health Statistics, CDC.

Cancer Rates in WA (2001)

Type

Incidenc
WA rank County
e/
nationally (high)
100,000

Breast

181.7

1st female San

Juan

Lung

70.1

9th female Mason

30th male

Melanom
a

37.6

1st female Pend

Oreille
5th male

Bladder

23.7

24th
female
8th male

Washington State Cancer Registry

(Adapted from Kate Davies et al. report (2005))

Pend
Oreille

Cancer
Cancer can be caused by two different types of
chemical substances genotoxic carcinogens
and nongenotoxic carcinogens.
Genotoxic chemicals are believed to have no
threshold amount below which they will NOT
cause cancer.
Nongenotoxic carcinogens are believed to have a
safe threshold quantity.

Hazard Assessment for Cancer

US EPA guidelines:
1.
2.
3.
4.
5.
6.

Group A: Carcinogenic to humans (20 chemical);

Group B1: Probably carcinogenic to humans based on
limited human data;
Group B2: Probably carcinogenic to humans based on
sufficient animal data, inadequate human evidence;
Group C: Possibly carcinogenic to humans;
Group D: Not classified for human carcinogenicity;
Group E: Evidence for non-carcinogenicity for
humans.

Cancer Slope Factor (Example)

A study of the potential of acrylonitrile to produce brain
tumors in Fischer 344 rats was conducted by
administering the carcinogen in drinking water for 24
months. The results of the study for female rats are
tabulated below:
excess deaths m dose rate (mg/kg-day)

(excess risk)

0.3802
m

0.0234
(dose, mg/kg-day) 16.27

Risk Characterization of Cancer

Risk is defined as the probability of developing
cancer (in excess of the background cancer
level) from a particular chemical is a subpopulation is exposed to that chemical over a
lifetime.

Risk f Hazard, Exposure

Thank you