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Genotoxicity Perspective on Exposure to Environmental and Occupational Toxins
1. Exposure to environmental and Occupational
toxins and Human Health: Genotoxicity
Perspective
Dr. Vikas D. Dighe, M.V.Sc, Ph.D.
Scientist ‘E’ and Head,
National Center for Preclinical Reproductive and Genetic Toxicology
ICMR-National Institute of Research in Reproductive Health, Parel, Mumbai.
Email: dighev@nirrh.res.in
2. Objective of Regulatory Toxicology
To protect the people and the environment
from the harmful effects of the chemicals.
Not only protection, but also communication of the risk.
Finally it is the perception and acceptance of the risk.
Pub Med Citation on “Cigarette smoke and cancer”
Research articles - 1725
Reviews - 317
3. Why we need regulatory toxicology &
regulations?
1937 - Sulfanilamide Tragedy
1961 - Thalidomide Tragedy
1962 - Silent spring
1970 - Non clinical studies raised concern
1976 - US FDA published GLP Regulations
1981 - OECD GLP Regulations
Around 10% of all drugs approved (1975 to 1999)
acquired a “Black box” warning due to ADRs and
were withdrawn (PDR)
4. Where from it emerged?
To
President Roosevelt
“ Tonight Mr. Roosevelt that little voice is stilled. The time I ever had occasion to call in a
doctor for her and she was given the Elixir of Sulfanilamide. To night our little home is
bleak and full of despair…….
Even the memory of her is mixed with sorrow for we can see her little body turning to and
fro and hear that little voice screaming with pain and it seems as it drives me insane……..
Tonight President Roosevelt as you enjoy your little grand children's of whom we read
about, it is my plea that you will take steps to prevent such sales of drugs that will take
little lives and leave such sufferings behind ……….”
Grieving Mrs. Nidiffer,
(after her daughter Joan's death)
Toxicology grow more by episodes arises
from real tragedies, rather than a clear, logical
progression.
5. The Essence of Regulatory Toxicology
The study report is the product of your scientific efforts and
labour. If the report is not accurate, complete and
substantial by the raw data, the conduct of a non clinical
study is of no real value to the sponsor or the regulator.
Often the health and safety of the general public may well
depend upon the results of a single toxicology safety study.
Toxicological Testing Handbook
Principles, Applications and Data Interpretation
2nd Edition, 2006, Edited by D. Jacobson-Kram and K.A. Keller
6. How Genetic Toxicity became a part of
Regulatory Testing
Year Event
1969 First Govt. recognition, DHEW
(Mutagenicity testing in health safety
decision)
1971 FDA, M. Legator, First genotoxic Govt.
contract research (SRI, Covance)
1973 NCI, E. Weisburger, Carcingenicity prediction
in S. typhimurium and E. coli
1975 NCI (ad hoc committee) S9 ( Mutagenicity &
Carcinogenicty Correlation
1980 NTP (NIEHS)
1980 EPA, Mutagenicity in health study
2004 OECD, Harmonization in test guidelines
7. The Basic Paradigm
Virtual universality of double-stranded DNA as the genetic material
Empirical correlations between mutagenicity and carcinogenicity
Toxicology testing Genetic toxicology
Surrogate system Surrogate cell or animal system
End point is also surrogate
Genetic toxicology has probably been the most introspective and self
critical of all areas of toxicology
Zeiger E. History & Rationale of Genetic Toxicity Testing:
An Impersonal and Sometimes Personal, View
Environ. Mol. Mutagen, 2004
8. The Endocrine System
The Endocrine system is the term for
multiple and diverse hormonal systems
in the mammalian organism, such as
thyroid hormones, hormones
originating from the pancreas, ovaries,
testes, adrenals or the brain
9. What is Endocrine Disruption
‘‘An endocrine disruptor is an exogenous substance or mixture that alters function(s) of
the endocrine system and consequently causes adverse health effects in an intact
organism, or its progeny, or (sub) populations’’ (WHO-IPCS, 2002)
Source: Thaddeus T. Schug et al. Minireview: Endocrine Disruptors: Past Lessons and Future Directions
10. Model of the endocrine systems targeted by EDCs
All major endocrine organs
are vulnerable to endocrine
disruption, including the HPA
axis, reproductive organs,
the pancreas, and the
thyroid gland.
EDCs are also known to
impact hormone-dependent
metabolic systems and brain
function
11. Common Sources
Environmental and
Occupational hazards
Heavy Metals
Industrial
Chemicals
Pharmaceutical
Drugs
Personal Care
Products
Pesticides
Herbicides and
Fungicides
Synthetic
Hormones
12. Common Sources of Exposure of Environmental and
Occupational Toxicants